JP2013530137A - Alkyldiamine derivatives and their use as antidepressants - Google Patents

Alkyldiamine derivatives and their use as antidepressants Download PDF

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JP2013530137A
JP2013530137A JP2013509442A JP2013509442A JP2013530137A JP 2013530137 A JP2013530137 A JP 2013530137A JP 2013509442 A JP2013509442 A JP 2013509442A JP 2013509442 A JP2013509442 A JP 2013509442A JP 2013530137 A JP2013530137 A JP 2013530137A
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建其 李
永勇 鄭
云鳳 廖
亞莉 李
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Abstract

本発明は以下の構造一般式のようなアルキルジアミン類誘導体又はその薬学的に許容される塩、及びその抗うつ薬としての使用を開示する。前記アルキルジアミン類誘導体は5-セロトニン、ノルアドレナリン及びドーパミンに対して三重再取り込みを阻害できる活性を有し、且つ薬物組成物の形式で、経口や注射等によりこのような治療を必要とする患者に投与することができる。
【化１】

Figure 2013530137
The present invention discloses alkyldiamine derivatives having the following general structural formula or pharmaceutically acceptable salts thereof, and their use as antidepressants. The alkyldiamine derivatives have an activity capable of inhibiting triple reuptake with respect to 5-serotonin, noradrenaline and dopamine, and are in the form of a drug composition for patients who need such treatment by oral or injection. Can be administered.
[Chemical 1]
Figure 2013530137

Description

本発明はアルキルジアミン類誘導体、及び該誘導体の抗うつ薬としての使用に関する。   The present invention relates to alkyldiamine derivatives and use of the derivatives as antidepressants.

うつ病は現代において最もよく見られる人間の心身の健康を脅かす精神疾患である。その発病率は世界人口の5％くらいを占め、人間の体の健康及び生活の質に大きな影響を与えている。2020年までに、うつ病は人間の健康を脅かし、寿命を縮める第二の重大疾患になると予想されている。   Depression is the most common mental illness that threatens human mental and physical health. Its incidence accounts for about 5% of the world population and has a major impact on human health and quality of life. By 2020, depression is expected to become the second major disease that threatens human health and shortens life expectancy.

現在、抗うつ薬の作用メカニズムは完全に解明されていない。明らかな治療効果を持つ薬剤は基本的に末梢神経シナプス部位に作用し、シナプス間隙の神経伝達物質レベルを調節することで治療作用を発揮する。その病因学の生物化学研究で明らかになっているのは、うつ病は主に中枢の5-セロトニン(5-HT)、ノルアドレナリン(NA)、ドーパミン(DA)、アセチルコリン(Ach)及びγ-アミノ酪酸(GABA)等5つの神経伝達物質に関係するということである。   Currently, the mechanism of action of antidepressants has not been fully elucidated. Drugs with clear therapeutic effects basically act on peripheral nerve synaptic sites and exert therapeutic effects by regulating neurotransmitter levels in the synaptic cleft. Biochemistry studies in its etiology reveal that depression is primarily central 5-serotonin (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (Ach) and γ-amino. It is related to five neurotransmitters such as butyric acid (GABA).

抗うつ薬は、早期の非選択的抗うつ薬と新型選択的再取り込み阻害薬の二種類に大きく分けられる。非選択的抗うつ薬は主にモノアミン酸化酵素阻害薬(MAOIs)と三環系抗うつ薬(TCAs)を含む。選択的再取り込み阻害薬は主に以下を含む：(1)フルオキセチン(Fluoxetine)やパロキセチン(Paroxetine)のような選択的5-セロトニン(5-HT) 再取り込み阻害薬(SSRIs)、(2)レボキセチン(Reboxitine)のようなノルアドレナリン(NA)再取り込み阻害薬(NRIs)、(3)ミルタザピン(Mirtazapine)のようなノルアドレナリン作動剤及び特異的5-HT再取り込み阻害薬(NDRIs)、(4)ベンラファクシン(Venlafaxine)やデュロキセチン(Duloxetine)のような5-HT・NA二重再取り込み阻害薬(SNRIs)、(5)チアネプチン(Tianeptine)のような5-HT再取り込み促進剤など。   Antidepressants can be broadly divided into two types: early non-selective antidepressants and new selective reuptake inhibitors. Non-selective antidepressants mainly include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Selective reuptake inhibitors mainly include: (1) selective 5-serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine, (2) reboxetine Noradrenaline (NA) reuptake inhibitors (NRIs) such as (Reboxitine), (3) noradrenaline agonists and specific 5-HT reuptake inhibitors (NDRIs) such as mirtazapine, (4) venlafa 5-HT / NA double reuptake inhibitors (SNRIs) such as Venlafaxine and Duloxetine, and (5) 5-HT reuptake promoters such as tianeptine.

既に多くの抗うつ薬が臨床に用いられているとはいえ、それらの中には反応率が低いものもあり、また、潜在的に副作用を有しているため、多くの患者は各種薬物治療を施しても効果が得られず、電気ショック療法に助けを求める場合もある。したがって、抗うつ薬の開発は依然として新規薬剤研究の焦点であり、多くの製薬業者がより優れた治療薬を開発することに多くの資金を投入している。   Although many antidepressants have already been used clinically, some have low response rates and potentially have side effects, so many patients are treated with various medications. In some cases, no effect is obtained, and electric shock therapy is sought for help. Therefore, the development of antidepressants remains the focus of new drug research, and many pharmaceutical companies have invested a lot in developing better therapeutics.

現在、抗うつ薬の世界的な研究趨勢は主に二つである。   Currently, there are mainly two global research trends in antidepressants.

一つ目は、従来薬物の二次開発である。これには1)薬物の新規適応症を更に開発することと、2)従来薬物の薬剤タイプを変えることが含まれる。   The first is the secondary development of conventional drugs. This includes 1) further developing new indications for drugs and 2) changing the drug type of conventional drugs.

二つ目は、新製品の更なる開発である。新規ターゲット又はマルチターゲットに作用する新しい構造タイプの化合物を見つけることによって従来の市販薬物より抗うつ作用に優れ、効き目が早く、かつ安全性の高い新型抗うつ薬を開発することである。   The second is the further development of new products. It is to develop a new type of antidepressant that is superior in anti-depressive action, faster in action and higher in safety than conventional commercially available drugs by finding a compound of a new structure type that acts on a new target or a multi-target.

現在、抗うつ新薬研究において、選択的三重再取り込み阻害薬の研究が重要視されており、従来の抗うつ薬の遅延型効果の問題、及び有効性、安全性の向上などの問題の解決が望まれている。三重再取り込み阻害薬は「広スぺクトラム」抗うつ薬(“broad spectrum” antidepressants)とも呼ばれ、同時に選択的にうつ病に密接に関連する三種のモノアミン伝達物質である5-HT、NA及びDAの再取り込みを阻害できる化合物を指す。   At present, research on selective triple reuptake inhibitors is emphasized in the research on antidepressant new drugs, and the problem of delayed effect of conventional antidepressants and the improvement of efficacy and safety are solved. It is desired. Triple reuptake inhibitors, also called “broad spectrum” antidepressants, are simultaneously 5-HT, NA, and three monoamine transmitters that are selectively associated with depression. A compound that can inhibit DA reuptake.

三重再取り込み阻害抗うつ薬は現在まだ臨床研究段階にある。例えば、DOVファーマスーティカル社により研究開発された三重再取り込み阻害薬DOV-21947は第2相臨床試験にあり、グラクソ・スミスクライン社とニューロサーチ社とが共同開発したNS-2359は現在抗うつ第2相臨床試験にある。これらモノアミン伝達物質三重再取り込み阻害抗うつ薬は効能が高く、効き目が早いなどの優位性を有し、正に抗うつ分野で注目の的となっている。我が国の抗うつ新規薬物の研究及び開発はまだ初歩的段階にあり、特に5-HT、NA及びDA系に作用する三重ルートの新規抗うつ薬の研究はより一層注目される重要課題となっている。   Triple reuptake inhibitor antidepressants are still in clinical research. For example, the triple reuptake inhibitor DOV-21947, researched and developed by DOV Pharmaceuticals, is in Phase II clinical trials, and NS-2359, co-developed by GlaxoSmithKline and Neurosearch, is currently antidepressant. It is in a phase 2 clinical trial. These monoamine transmitter triple reuptake inhibitor antidepressants have advantages such as high efficacy and fast efficacy, and are attracting attention in the field of antidepressants. The research and development of new antidepressant drugs in Japan is still in the elementary stage, and especially the research of the triple route new antidepressant acting on 5-HT, NA and DA system has become an important issue that attracts more attention. Yes.

発明が解決しようとする課題
本発明が解決しようとする技術課題の一つ目は、うつ病治療の需要を満足できるよう、従来技術に存在していた効き目が遅い、治療効果が小さい、副作用が大きい、安全性が低いなどの欠点を克服したアルキルジアミン類誘導体を開示することである。 Problems to be Solved by the Invention The first of the technical problems to be solved by the present invention is that the effects existing in the prior art are slow, the therapeutic effects are small, and there are side effects so as to satisfy the demand for treatment of depression. It is to disclose alkyldiamine derivatives that have overcome the disadvantages such as large size and low safety.

本発明が解決しようとする技術課題の二つ目は、上記誘導体の抗うつ薬としての使用を開示することである。   The second technical problem to be solved by the present invention is to disclose the use of the above derivative as an antidepressant.

課題を解決するための手段
本発明に記載のアルキルジアミン類誘導体は以下の構造一般式を有する化合物又はその薬用できる塩であり、その塩は0.5-3分子の結晶水を含む： Means for Solving the Problems The alkyldiamine derivatives described in the present invention are compounds having the following general structural formula or pharmaceutically acceptable salts thereof, and the salts contain 0.5-3 molecules of crystal water:

Figure 2013530137
Figure 2013530137

但し、   However,

Figure 2013530137
Figure 2013530137

又は、任意的に置換された、チエニル基、フリル基、ピリミジニル基、ピリダジニル基、ピラジニル基、オキサゾール基、イソキサゾール基、チアゾール基、イソチアゾール基、イミダゾール基又はピラゾリルから選択したヘテロアリール基を示し、かつArは未置換ベンゼン環とすることはできない。   Or an optionally substituted heteroaryl group selected from thienyl, furyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazole, isoxazole, thiazole, isothiazole, imidazole or pyrazolyl; And Ar cannot be an unsubstituted benzene ring.

R1は水素又はC1−C5のアルキル基を示す。 R 1 represents hydrogen or a C 1 -C 5 alkyl group.

R2、R3はそれぞれ水素、C1−C5のアルキル基、C1−C5のハロゲン化アルキル基、C1−C5のヒロドキシアルキル基、C1−C5のアルコキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ベンジル基又は置換ベンジル基等のうちの一種を示し、かつR2、R3は同時に水素ではない。 R 2 and R 3 are each hydrogen, C 1 -C 5 alkyl group, C 1 -C 5 halogenated alkyl group, C 1 -C 5 hydroxyalkyl group, C 1 -C 5 alkoxy group, One of C 5 or C 6 alicyclic ring, phenyl group, substituted phenyl group, benzyl group or substituted benzyl group is shown, and R 2 and R 3 are not hydrogen at the same time.

又はR2、R3及びNは5員環〜7員環の脂肪環に連なり、該脂肪環に1個のN又はO又はSを含有してもよく、かつNにはR7で置換されてもよい。 Or R 2 , R 3 and N are linked to a 5-membered to 7-membered alicyclic ring, and the alicyclic ring may contain one N, O or S, and N is substituted with R 7 May be.

R4, R5, R6 はそれぞれ水素、C1−C3のアルキル基又はアルコキシ基、C1−C3のハロゲン化アルキル基、C1−C3のハロゲン化アルコキシ基、ベンジルオキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ヒドロキシ基、アミノ基、置換アミノ基、ハロゲン、カルボン酸基、カルボン酸エステル基、ニトロ基又はシアノ基等のうちの一種を示す。 R 4 , R 5 and R 6 are each hydrogen, C 1 -C 3 alkyl group or alkoxy group, C 1 -C 3 halogenated alkyl group, C 1 -C 3 halogenated alkoxy group, benzyloxy group, One of C 5 or C 6 alicyclic ring, phenyl group, substituted phenyl group, hydroxy group, amino group, substituted amino group, halogen, carboxylic acid group, carboxylic acid ester group, nitro group, cyano group and the like is shown.

R7はC1−C5のアルキル基、C1−C5のハロゲン化アルキル基、C1−C5のヒロドキシアルキル基、C1−C5のアルコキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ベンジル基又は置換ベンジル基等のうちの一種を示す。 R 7 is a C 1 -C 5 alkyl group, a C 1 -C 5 halogenated alkyl group, a C 1 -C 5 hydroxyalkyl group, a C 1 -C 5 alkoxy group, a C 5 or C 6 One of an alicyclic ring, a phenyl group, a substituted phenyl group, a benzyl group, or a substituted benzyl group is shown.

YはC、N、Oを示す。但し、NはC1−C3のアルキル基、C1−C3のハロゲン化アルキル基、C1−C3のヒロドキシアルキル基、フェニル基、置換フェニル基、ベンジル基、置換ベンジル基、芳香族複素環又は置換芳香族複素環で置換できる。 Y represents C, N, or O. However, N is the C 1 -C 3 alkyl group, a halogenated alkyl group of C 1 -C 3, C 1 -C 3 Hiro de alkoxyalkyl group, a phenyl group, a substituted phenyl group, a benzyl group, substituted benzyl group, It can be substituted with an aromatic heterocycle or a substituted aromatic heterocycle.

前記置換フェニル基又は置換フェニル基はベンゼン環に1〜4個の置換基を有し、その置換基はR4、R5、R6である。 The substituted phenyl group or the substituted phenyl group has 1 to 4 substituents on the benzene ring, and the substituents are R 4 , R 5 and R 6 .

前記置換アミノ基はアミノ基にC1−C3のアルキル基又はC1−C3のハロゲン化アルキル基を有する基である。 The substituted amino group is a group having a halogenated alkyl group of the alkyl group or C 1 -C 3 of C 1 -C 3 amino groups.

XはC、Nを示す。   X represents C and N.

ZはC、S、N、Oを含む五員又は六員飽和環、五員又は六員不飽和環を示す。   Z represents a 5-membered or 6-membered saturated ring containing C, S, N, or O, or a 5-membered or 6-membered unsaturated ring.

m = 0、1、2であり、n = 1、 2である。   m = 0, 1, 2 and n = 1, 2.

好ましい化合物は以下を含む：
VI-1 N,N-ジエチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-2 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-3 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピペラジン-1-イル)-プロピルアミン、
VI-4 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン、
VI-5 N-メチル-N-ベンジル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン、
VI-6 4-(3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン、
VI-7 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ピペリジニル-プロピルアミン、
VI-8 N,N-ジメチル-3-(4-クロロフェニル)-3-モルホリニル-プロピルアミン、
VI-9 4-(3-(4-クロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン、
VI-10 N,N-ジメチル-3-(4-メチルフェニル)-3-モルホリニル-プロピルアミン、
VI-11 4-(3-(4-メチルピペラジン-1-イル)-1-(4-メチルフェニル)プロピル)モルホリン、
VI-12 4-(3-(4-メチルフェニル)-3-(モルホリニル)プロピル)ピロール、
VI-13 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-14 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-15 N-メチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-16 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-17 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-18 N-メチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-19 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-20 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-21 N-メチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-22 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-イル-プロピルアミン、
VI-23 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン、
VI-24 N-メチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン、
VI-25 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-26 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-27 N-メチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-28 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-29 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-30 N-メチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-31 N,N-ジメチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-32 N-メチル-N-ベンジル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-33 N-メチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-34 N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-モルホリニル-プロピルアミン、
VI-35 N-メチル-N-ベンジル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-モルホリニル-プロピルアミン、
VI-36 N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-37 N,N-ジメチル-3-(4-メトキシフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-38 N,N-ジメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-39 N,N,2-トリメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-40 N,N-ジメチル-2-((3,4-ジクロロフェニル)(モルホリン)メチル)-1-ヘプチルアミン、
VI-41 N,N-ジメチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-42 N-メチル-N-ベンジル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-43 N-メチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-44 N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-モルホリニル-ブチルアミン、
VI-45 N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-(ピペラジン-1-イル)-ブチルアミン、
VI-46 N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-モルホリニル-ブチルアミン、
VI-47 N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-(ピペラジン-1-イル)-ブチルアミン、
VI-48 N,N-ジメチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-49 N-メチル-N-ベンジル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-50 N-メチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-51 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-ベンジルピペラジニル)-プロピルアミン、
VI-52 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-(3-(トリフルオロメチル)フェニル)ピペラジニル)-プロピルアミン、
VI-53 N-メチル-N-ベンジル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン、
VI-54 N-メチル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン、
VI-55 N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-56 N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-57 N-メチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-58 N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-59 N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-60 N-メチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-61 N,N-ジメチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-62 N-メチル-N-ベンジル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-63 N-メチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン
又はその薬用できる塩。 Preferred compounds include:
VI-1 N, N-diethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-2 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-3 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (piperazin-1-yl) -propylamine,
VI-4 N, N-dimethyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine,
VI-5 N-methyl-N-benzyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine,
VI-6 4- (3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine,
VI-7 N, N-dimethyl-3- (3,4-dichlorophenyl) -3-piperidinyl-propylamine,
VI-8 N, N-dimethyl-3- (4-chlorophenyl) -3-morpholinyl-propylamine,
VI-9 4- (3- (4-Chlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine,
VI-10 N, N-dimethyl-3- (4-methylphenyl) -3-morpholinyl-propylamine,
VI-11 4- (3- (4-methylpiperazin-1-yl) -1- (4-methylphenyl) propyl) morpholine,
VI-12 4- (3- (4-methylphenyl) -3- (morpholinyl) propyl) pyrrole,
VI-13 N, N-dimethyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-14 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-15 N-methyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-16 N, N-dimethyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-17 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-18 N-methyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-19 N, N-dimethyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-20 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-21 N-methyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-22 N, N-dimethyl-3- (benzothiophen-2-yl) -3-piperidinyl-yl-propylamine,
VI-23 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine,
VI-24 N-methyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine,
VI-25 N, N-dimethyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-26 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-27 N-methyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-28 N, N-dimethyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-29 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-30 N-methyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-31 N, N-dimethyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-32 N-methyl-N-benzyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-33 N-methyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-34 N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine,
VI-35 N-methyl-N-benzyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine,
VI-36 N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-37 N, N-dimethyl-3- (4-methoxyphenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-38 N, N-dimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine,
VI-39 N, N, 2-trimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine,
VI-40 N, N-dimethyl-2-((3,4-dichlorophenyl) (morpholine) methyl) -1-heptylamine,
VI-41 N, N-dimethyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-42 N-methyl-N-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-43 N-methyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-44 N, N-dimethyl-4- (3,4-dichlorophenyl) -4-morpholinyl-butylamine,
VI-45 N, N-dimethyl-4- (3,4-dichlorophenyl) -4- (piperazin-1-yl) -butylamine,
VI-46 N, N-dimethyl-4- (benzothiophen-3-yl) -4-morpholinyl-butylamine,
VI-47 N, N-dimethyl-4- (benzothiophen-3-yl) -4- (piperazin-1-yl) -butylamine,
VI-48 N, N-dimethyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-49 N-methyl-N-benzyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-50 N-methyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-51 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4-benzylpiperazinyl) -propylamine,
VI-52 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4- (3- (trifluoromethyl) phenyl) piperazinyl) -propylamine,
VI-53 N-methyl-N-benzyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine,
VI-54 N-methyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine,
VI-55 N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-56 N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-57 N-methyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-58 N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-59 N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-60 N-methyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-61 N, N-dimethyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine,
VI-62 N-methyl-N-benzyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine,
VI-63 N-methyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine or a pharmaceutically acceptable salt thereof.

前記化合物の構造式を表1に示す。   The structural formula of the compound is shown in Table 1.

Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137
Figure 2013530137

本発明の化合物は以下の合成方法で調製できる。   The compounds of the present invention can be prepared by the following synthetic methods.

芳香環化合物（I）と相応のアシルクロライド化合物（VII）をAlCl3触媒でF-C反応させて相応のハロゲン化アリールアルキルケトン（II）を得て、中間体（II）と相応のアンモニア化合物（VIII）を置換反応させて中間体（III）を得る。該中間体（III）は相応のアリールケトン（IV）、アンモニア化合物（VIII）及びパラホルムアルデヒドによりMannich反応させて調製してもよい。中間体（III）をNaBH4還元反応させて化合物（V）を得る。中間体（V）と塩化パラトルエンスルホニルを反応させた後、化合物（IX）を入れて最終生成物（VI）を得る： The aromatic ring compound (I) and the corresponding acyl chloride compound (VII) are subjected to FC reaction with an AlCl 3 catalyst to obtain the corresponding halogenated arylalkylketone (II), and the intermediate (II) and the corresponding ammonia compound (VIII) ) To obtain an intermediate (III). The intermediate (III) may be prepared by Mannich reaction with the corresponding aryl ketone (IV), ammonia compound (VIII) and paraformaldehyde. Intermediate (III) is subjected to a NaBH 4 reduction reaction to obtain compound (V). After reacting intermediate (V) with p-toluenesulfonyl chloride, compound (IX) is added to give final product (VI):

Figure 2013530137
Figure 2013530137

但し、X=Cl、Brであり、Ar、 R1、 R2、 R3、 Y、 m、 nは前記と同じである。 However, X = Cl and Br, and Ar, R 1 , R 2 , R 3 , Y, m, and n are the same as described above.

前記過程において、
a: AlCl3、CH2Cl2。又はAlCl3、70℃。 In the process,
a: AlCl 3 , CH 2 Cl 2 . Or AlCl 3 , 70 ° C.

b: EtOH 還流。又はEtN(i-Pr)2、CH3CN。 b: EtOH reflux. Or EtN (i-Pr) 2 , CH 3 CN.

c: パラホルムアルデヒド、濃塩酸、95％エタノール。   c: Paraformaldehyde, concentrated hydrochloric acid, 95% ethanol.

d: NaBH4、CH3OH。 d: NaBH 4 , CH 3 OH.

e: (1)TsCl、N(Et)3。(2) IX、K2CO3。 e: (1) TsCl, N (Et) 3 . (2) IX, K 2 CO 3 .

前記芳香環化合物（I）、アシルクロライド化合物（VII）、アンモニア化合物（VIII）、アリールケトン（IV）及びシクロアルキルアミン（IX）は市販購入又は実施例に記載の方法により調製できる。   The aromatic ring compound (I), acyl chloride compound (VII), ammonia compound (VIII), aryl ketone (IV) and cycloalkylamine (IX) can be purchased commercially or prepared by the methods described in the Examples.

本発明にかかる前記アラルキルアルコールピペリジン誘導体は5-HT、NA及びDAの再取り込みに対して三重阻害作用を有し、抗うつ薬の調製に用いることができる。   The aralkyl alcohol piperidine derivative according to the present invention has a triple inhibitory action on the reuptake of 5-HT, NA and DA, and can be used for the preparation of an antidepressant.

本発明の誘導体は組成物の形式で、経口や注射等によりこのような治療を必要とする患者に投与することができる。   The derivative of the present invention can be administered to a patient in need of such treatment by oral or injection in the form of a composition.

前記組成物には治療有効量の上記化合物又はその薬用できる塩および医学的に許容される担体が含まれる。   The composition includes a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

かかる担体とは薬学分野でよくみられる担体を指し、例えば、水のような希釈剤、賦形剤；セルロース誘導体、ゼラチン、ポリビニルピロリドン等のような粘着剤；でんぷん等のような充填剤；炭酸カルシウム、重炭酸ナトリウム等のような崩壊剤がある。また、組成物に香味剤、甘味料等のような他の補助剤を加えることもできる。   Such a carrier refers to a carrier often used in the pharmaceutical field. For example, a diluent such as water, an excipient; an adhesive such as a cellulose derivative, gelatin, or polyvinylpyrrolidone; a filler such as starch; There are disintegrants such as calcium, sodium bicarbonate and the like. Also, other adjuvants such as flavoring agents, sweeteners and the like can be added to the composition.

経口投与の場合、錠剤、粉剤又はカプセル等、一般的な固体製剤に調製することができる。注射投与の場合、注射液に調製することができる。   In the case of oral administration, it can be prepared into a general solid preparation such as a tablet, powder or capsule. In the case of injection administration, it can be prepared as an injection solution.

本発明の組成物の各種タイプの薬剤は医学分野での一般的な方法で調製でき、そのうち、活性成分の含有量は0.1%〜99.5%(重量比)である。   Various types of drugs of the composition of the present invention can be prepared by a general method in the medical field, and the content of the active ingredient is 0.1% to 99.5% (weight ratio).

本発明の投与量は投与経路、患者の年齢、体重、治療する疾患のタイプおよび重症度などにより変えることができ、1日の投与量は5-30mg/kg体重(経口)又は1-10mg/kg体重(注射)である。   The dosage of the present invention can vary depending on the route of administration, patient age, body weight, type and severity of the disease to be treated, and the daily dosage is 5-30 mg / kg body weight (oral) or 1-10 mg / kg body weight (injection).

本発明の化合物又はその薬用できる塩は動物試験においてうつ病に対する拮抗作用を示した。   The compound of the present invention or a pharmaceutically acceptable salt thereof showed an antagonistic action against depression in animal tests.

発明の効果
本発明者らは、本発明の誘導体の抗うつ作用が現在臨床上で使用されている従来の単一的な作用メカニズムの抗うつ薬よりもより良い治療効果、より広い適応症を有し、副作用が小さいことを発見した。 EFFECT OF THE INVENTION The present inventors have shown that the antidepressant action of the derivative of the present invention has a better therapeutic effect and broader indications than the conventional single-action mechanism antidepressant currently used clinically. It has been found that side effects are small.

一般合成法一：
ハロゲン化のハロゲン化アリールアルキルケトン（II）の調製
方法A：
芳香環化合物(I) (0.2mol)をCH2Cl2 (200mL)に溶かし、氷バスで、AlCl3(0.24mol)を分割的に加えるとともに、内温0-5℃に保ちながら30分攪拌する。内温＜5℃に制御しながら、相応のアシルクロライド（VII）(0.22mol)のCH2Cl2(100mL)溶液を滴下し、滴下終了後、室温まで上げ、3時間反応させ、TLC(酢酸エチル：石油エーテル=1：15)により完全に反応し終わったことを確認する。反応液を60mLの氷水に入れ、絶えず攪拌し、分液し、有機層飽和食塩水（50mL)で洗浄し、有機層無水MgSO4で乾燥させた後、ろ過濃縮し、無水エタノール（50mL）でスラリー化し、純粋なハロゲン化アリールアルキルケトン（II）を得る。収率は70-90％。 General Synthesis Method 1:
Preparation of halogenated halogenated aryl alkyl ketone (II) Method A:
Dissolve aromatic ring compound (I) (0.2 mol) in CH 2 Cl 2 (200 mL), add AlCl 3 (0.24 mol) in portions in an ice bath, and stir for 30 minutes while maintaining the internal temperature at 0-5 ° C. To do. While controlling the internal temperature <5 ° C., a corresponding solution of acyl chloride (VII) (0.22 mol) in CH 2 Cl 2 (100 mL) was added dropwise. After completion of the addition, the solution was raised to room temperature, reacted for 3 hours, and TLC (acetic acid Ethyl: petroleum ether = 1: 15) confirms complete reaction. The reaction mixture was poured into 60 mL of ice water, constantly stirred, separated, washed with organic layer saturated brine (50 mL), dried over organic layer anhydrous MgSO 4 , filtered and concentrated with absolute ethanol (50 mL). Slurry to obtain the pure halogenated aryl alkyl ketone (II). Yield 70-90%.

方法B：
芳香環化合物（I）（0.2mol）にAlCl3(0.2mol)を加え、70℃まで加熱し、攪拌下で、相応のアシルクロライド（VII）（0.2mol）を滴下し、滴下終了後、70℃で8時間反応させ、TLC(酢酸エチル：石油エーテル=1：15)により完全に反応し終わったことを確認する。室温まで冷まし、ジクロロメタン（100mL）を加えた後、50mLの氷水に入れて絶えず攪拌し、分液し、有機層飽和食塩水（50mL)で1回洗浄し、有機層無水MgSO4で乾燥させた後、ろ過収縮し、無水エタノール（50mL）でたたきほぐし、純粋なハロゲン化アリールアルキルケトン（II）を得る。収率は80-90％。 Method B:
AlCl 3 (0.2 mol) is added to aromatic ring compound (I) (0.2 mol), heated to 70 ° C., and the corresponding acyl chloride (VII) (0.2 mol) is added dropwise with stirring. The reaction is carried out at 0 ° C. for 8 hours, and it is confirmed by TLC (ethyl acetate: petroleum ether = 1: 15) that the reaction has been completed. After cooling to room temperature and adding dichloromethane (100 mL), the mixture was constantly stirred in 50 mL of ice water, separated, washed once with organic layer saturated brine (50 mL), and dried over anhydrous MgSO 4 . Thereafter, the solution is contracted by filtration and beaten with absolute ethanol (50 mL) to obtain a pure halogenated aryl alkyl ketone (II). Yield 80-90%.

一般合成法二：
アラルキルケトンアミン中間体（III）の調製
方法A:
ハロゲン化アリールアルキルケトン（II）(0.1mol)と原料アンモニア化合物（VIII）（0.5mol）を無水エタノール（100mL）に溶かし、3時間加熱還流反応し、TLC(ジクロロメタン：メタノール=20：1)により原料（II）が完全に反応し終わったことを確認する。溶剤を濃縮乾固し、ジクロロメタン（100mL）と飽和食塩水（40mL）を入れて20分攪拌した後、分液し、有機層を濃度5％の希塩酸溶液（30mL）で洗浄した後に分液し、有機層を無水MgSO4で乾燥させてろ過濃縮し、得られた粗製品を酢酸エチル（30mL）に溶かし、塩酸エタノールを加えて塩酸塩にし、中間体（III）を得る。収率は70-95％（中間体IIで計算）。 General synthesis method 2:
Preparation of Aralkylketoneamine Intermediate (III) Method A:
Halogenated aryl alkyl ketone (II) (0.1 mol) and raw ammonia compound (VIII) (0.5 mol) are dissolved in absolute ethanol (100 mL), heated and refluxed for 3 hours, and subjected to TLC (dichloromethane: methanol = 20: 1). Confirm that the raw material (II) has completely reacted. Concentrate the solvent to dryness, add dichloromethane (100 mL) and saturated brine (40 mL), stir for 20 minutes, then separate the layers, wash the organic layer with 5% strength dilute hydrochloric acid solution (30 mL), and then separate. The organic layer is dried over anhydrous MgSO 4 and concentrated by filtration. The obtained crude product is dissolved in ethyl acetate (30 mL), and hydrochloride is added with hydrochloric acid ethanol to obtain intermediate (III). Yield 70-95% (calculated with intermediate II).

方法B:
ハロゲン化アリールアルキルケトン（II）(0.1mol)と原料アンモニア化合物（VIII）の塩酸塩（0.1mol）をアセトニトリル（100mL）に溶かし、ジイソプロピルエチルアミン(0.2mol)を加え、室温で12時間反応させ、 TLC (ジクロロメタン：メタノール=20：1) により原料（II）が完全に反応し終わったことを確認する。溶剤を濃縮乾固し、ジクロロメタン（100mL）と飽和食塩水（40mL）を入れて20分攪拌した後、分液し、有機層を濃度5％の希塩酸溶液（30mL）で洗浄した後に分液し、有機層を無水MgSO4で乾燥させてろ過濃縮し、得られた粗製品を酢酸エチル（30mL）に溶かし、塩酸エタノールを加えて塩酸塩にし、中間体（III）を得る。収率は60-85％（中間体IIで計算）。 Method B:
Dissolve the halogenated aryl alkyl ketone (II) (0.1 mol) and the hydrochloride (0.1 mol) of the raw material ammonia compound (VIII) in acetonitrile (100 mL), add diisopropylethylamine (0.2 mol), and react at room temperature for 12 hours. TLC (dichloromethane: methanol = 20: 1) confirms that the raw material (II) has completely reacted. Concentrate the solvent to dryness, add dichloromethane (100 mL) and saturated brine (40 mL), stir for 20 minutes, then separate the layers, wash the organic layer with 5% strength dilute hydrochloric acid solution (30 mL), and then separate. The organic layer is dried over anhydrous MgSO 4 and concentrated by filtration. The obtained crude product is dissolved in ethyl acetate (30 mL), and hydrochloride is added with hydrochloric acid ethanol to obtain intermediate (III). Yield 60-85% (calculated with intermediate II).

方法C:
アリールケトン化合物（IV）(0.1mol)、相応の原料アンモニア（VIII）の塩酸塩（0.11mol）及びパラホルムアルデヒド（0.13mol）を95％エタノール（20mL）に溶かし、重量濃度36％の濃塩酸（0.2mL）を入れ、5時間還流反応し、TLC (ジクロロメタン：メタノール=20：1)により原料（IV）が完全に反応し終わったことを確認する。溶剤を濃縮乾固し、ジクロロメタン（100mL）と飽和炭酸水素ナトリウム溶液（40mL）を入れて20分攪拌した後、分液し、有機層を重量濃度5％の希塩酸溶液（30mL）で洗浄した後、分液し、有機層を無水MgSO4で乾燥させてろ過濃縮し、得られた粗製品を酢酸エチル（30mL）に溶かし、塩酸エタノールを加えて塩酸塩にし、中間体（III）を得る。収率は70-90％（中間体IVで計算）。 Method C:
Aryl ketone compound (IV) (0.1 mol), the corresponding raw material ammonia (VIII) hydrochloride (0.11 mol) and paraformaldehyde (0.13 mol) are dissolved in 95% ethanol (20 mL), and concentrated hydrochloric acid with a weight concentration of 36% ( 0.2 mL), and refluxed for 5 hours, confirming that the raw material (IV) has completely reacted by TLC (dichloromethane: methanol = 20: 1). Concentrate the solvent to dryness, add dichloromethane (100 mL) and saturated sodium hydrogen carbonate solution (40 mL), stir for 20 minutes, separate the layers, and wash the organic layer with dilute hydrochloric acid solution (30 mL) with a weight concentration of 5%. The organic layer is dried over anhydrous MgSO 4 and concentrated by filtration. The obtained crude product is dissolved in ethyl acetate (30 mL), and hydrochloric acid ethanol is added to obtain a hydrochloride to obtain an intermediate (III). Yield 70-90% (calculated with intermediate IV).

一般合成法三：
アラルキルケトンアミン中間体（V）の調製
アラルキルケトンアミン中間体（III）（0.05mol）をメタノール（50mL）に溶かし、室温条件で水酸化ホウ素ナトリウム（0.05mol）を分割的に加え、室温に保ちながら3時間攪拌反応させる。 TLC (ジクロロメタン：メタノール=15：1)により原料（III）が完全に反応し終わったことを確認する。溶剤を濃縮乾固し、ジクロロメタン（60mL）と飽和食塩水（30mL）を入れた20分攪拌した後、分液し、有機層を無水MgSO4で乾燥させてろ過濃縮し、得られた粗製品を酢酸エチル（20mL）に溶かし、塩酸エタノールを加えて塩酸塩にし、中間体（V）を得る。収率は80-95％。 General Synthesis Method 3:
Preparation of aralkyl ketone amine intermediate (V) Dissolve aralkyl ketone amine intermediate (III) (0.05 mol) in methanol (50 mL), add sodium borohydride (0.05 mol) in portions at room temperature, and keep at room temperature. The reaction is allowed to stir for 3 hours. It is confirmed by TLC (dichloromethane: methanol = 15: 1) that the raw material (III) has completely reacted. The solvent was concentrated to dryness, dichloromethane (60 mL) and saturated brine (30 mL) were added, and the mixture was stirred for 20 min., And the layers were separated. The organic layer was dried over anhydrous MgSO 4 and concentrated by filtration. Is dissolved in ethyl acetate (20 mL) and ethanolic hydrochloric acid is added to form a hydrochloride salt to obtain intermediate (V). Yield 80-95%.

一般合成法四：
アルキルジアミン類化合物（VI）の調製
アラルキルケトンアミン中間体（V）（0.03mol）をアセトニトリル（50mL）に溶かし、室温条件で、トリエチルアミン（0.036mol）を加え、攪拌下で塩化パラトルエンスルホニル（0.033mol）を加え、室温で12時間反応させ、TLC (ジクロロメタン：メタノール=15：1)により原料（V）が完全に反応し終わったことを確認する。シクロアルキルアミン（IX）（0.09mol）と炭酸カリウム（0.03mol）を加え、室温で8時間反応させる。TLC (ジクロロメタン：メタノール=15：1)により完全に反応し終わったことを確認する。溶剤を濃縮乾固し、ジクロロメタン（60mL）と飽和食塩水（20mL）を入れて20分攪拌した後、分液し、有機層を濃度5％の希塩酸溶液（20mL）で洗浄した後に分液し、有機層を無水MgSO4で乾燥させてろ過濃縮し、得られた粗製品を酢酸エチル（10mL）に溶かし、塩酸エタノールを加えて塩酸塩にし、目的物（VI）の塩酸塩を得る。収率は40-60％。 General Synthesis Method 4:
Preparation of alkyldiamine compounds (VI) Aralkylketoneamine intermediate (V) (0.03 mol) was dissolved in acetonitrile (50 mL), triethylamine (0.036 mol) was added at room temperature, and paratoluenesulfonyl chloride (0.033 mol) was stirred. mol) is added and allowed to react at room temperature for 12 hours, and it is confirmed by TLC (dichloromethane: methanol = 15: 1) that the raw material (V) has completely reacted. Add cycloalkylamine (IX) (0.09 mol) and potassium carbonate (0.03 mol) and react at room temperature for 8 hours. Confirm complete reaction by TLC (dichloromethane: methanol = 15: 1). Concentrate the solvent to dryness, add dichloromethane (60 mL) and saturated brine (20 mL), stir for 20 minutes, then separate the layers, wash the organic layer with 5% strength dilute hydrochloric acid solution (20 mL), and separate the layers. The organic layer is dried over anhydrous MgSO 4 and concentrated by filtration. The obtained crude product is dissolved in ethyl acetate (10 mL), and hydrochloride is added with hydrochloric acid ethanol to obtain the hydrochloride of the target product (VI). Yield 40-60%.

実施例 1
N,N-ジエチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-1）塩酸塩の調製
1,2-ジクロロベンゼン（0.1mol）にAlCl3(0.1mol)を加え、 70℃まで加熱し、撹拌下で、3-クロロプロピオン酸クロライド（0.11mol）を滴下し、一般合成法一の方法Bで操作し、3-クロロ-1-(3,4-ジクロロフェニル)-アセトン 20.5 g（白色固体）を得る。収率は86.9%（1,2-ジクロロベンゼンで計算）。MS(m/z): 236.1[M+1]+。 Example 1
Preparation of N, N-diethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-1) hydrochloride
Add AlCl 3 (0.1 mol) to 1,2-dichlorobenzene (0.1 mol), heat to 70 ° C, add dropwise 3-chloropropionic acid chloride (0.11 mol) under stirring, and use the same general synthesis method Operate with B to obtain 20.5 g (white solid) of 3-chloro-1- (3,4-dichlorophenyl) -acetone. Yield 86.9% (calculated with 1,2-dichlorobenzene). MS (m / z): 236.1 [M + 1] + .

3-クロロ-1-(3,4-ジクロロフェニル)-アセトン（0.05mol）、ジエチルアミン（0.05mol）、ジイソプロピルエチルアミン(0.1mol) をアセトニトリル（100mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物12.0 gを得る。収率は77.7%。MS(m/z): 274.2[M+1]+。 Dissolve 3-chloro-1- (3,4-dichlorophenyl) -acetone (0.05 mol), diethylamine (0.05 mol), diisopropylethylamine (0.1 mol) in acetonitrile (100 mL), and operate in Method B of General Synthesis Method 2. To give 12.0 g of a white solid product. Yield 77.7%. MS (m / z): 274.2 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）の中で、一般合成法三で操作し、白色固体2.9 gを得る。収率は93.2%。MS(m/z): 276.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.9 g of a white solid. Yield 93.2%. MS (m / z): 276.1 [M + 1] + .

前記生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、N,N-ジエチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-1）の塩酸塩（白色固体）1.7 gを得る。収率53.1%。Mp = 249.3-252.7℃，MS(m/z): 329.2[M+1]+。 The product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL) and operated by General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) Is added to obtain 1.7 g of a hydrochloride salt (white solid) of N, N-diethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-1). Yield 53.1%. Mp = 249.3-252.7 ° C, MS (m / z): 329.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 1.13-1.16 (t, J=7.2Hz, 6H, -NCH2 CH 3 ), 1.85-1.98 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.58-2.61 (m, 2H, -CH 2 CH2N-), 2.61-2.83 (m, 2H, -NCH 2 CH2CH2 CH 2 N-), 2.91-2.96 (m, 2H, -CH2 CH 2 N-), 3.06 (m, 4H, -NCH 2 CH3), 3.19 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 3.74 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 4.63 (s, 1H, Ar-CH-), 7.75-7.77 (dd, J1=8.4Hz, J2=3.2Hz, 2H, Ar-H), 8.10 (s, 1H, Ar-H), 10.76 (br, 1H, HCl, +D2O消失), 12.14 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 1.13-1.16 (t, J = 7.2Hz, 6H, -NCH 2 CH 3 ), 1.85-1.98 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N -), 2.58-2.61 (m, 2H, -CH 2 CH 2 N-), 2.61-2.83 (m, 2H, -N CH 2 CH 2 CH 2 CH 2 N-), 2.91-2.96 (m, 2H, -CH 2 CH 2 N-), 3.06 (m, 4H, -N CH 2 CH 3 ), 3.19 (m, 1H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.74 (m, 1H,- N CH 2 CH 2 CH 2 CH 2 N-), 4.63 (s, 1H, Ar-CH-), 7.75-7.77 (dd, J 1 = 8.4Hz, J 2 = 3.2Hz, 2H, Ar-H), 8.10 (s, 1H, Ar- H), 10.76 (br, 1H, HCl, + D 2 O disappeared), 12.14 (br, 1H, HCl, + D 2 O disappeared).

実施例 2
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-2）塩酸塩の調製
3-クロロ-1-(3,4-ジクロロフェニル)-アセトン（0.05mol）、ジメチルアミン水溶液（0.25mol）を無水エタノール（100mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物11.5 gを得る。収率は81.9%。MS(m/z): 246.1[M+1]+。 Example 2
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-2) hydrochloride
3-Chloro-1- (3,4-dichlorophenyl) -acetone (0.05 mol) and dimethylamine aqueous solution (0.25 mol) are dissolved in absolute ethanol (100 mL) and operated by General Synthesis Method 2 Method A to produce a white solid. 11.5 g of product is obtained. Yield 81.9%. MS (m / z): 246.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.65 gを得る。収率は93.6%。MS(m/z): 248.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.65 g of a white solid. Yield 93.6%. MS (m / z): 248.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、，得N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-2）の塩酸塩（白色固体）1.4 gを得る。収率は47.0%。Mp = 266.5-268.6℃， MS(m/z): 301.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) ) To obtain 1.4 g of hydrochloride salt (white solid) of N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-2) . Yield 47.0%. Mp = 266.5-268.6 ° C, MS (m / z): 301.2 [M + 1] + .

1H NMR (CDCl3-d): δ: 1.80-1.99 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.54-2.55 (d, J=4.8Hz, 2H, -CH 2 CH2N-), 2.60-2.61 (d, J=4.8Hz, 2H, -CH2 CH 2 N-), 2.61 (s, 6H, N(CH3)2), 2.57-2.70 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 2.91-2.92 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 3.15-3.17 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 3.73-3.74 (m, 1H, -NCH 2 CH2CH2 CH 2 N-), 4.72 (s, 1H, Ar-CH-), 7.33-7.35 (d, J=8.4Hz, 1H, Ar-H), 7.68-7.70 (dd, J1=2.0Hz, J2=8.0Hz, 1H, Ar-H), 7.82 (d, J=2.0Hz, 1H, Ar-H), 11.70 (br, 1H, HCl, +D2O消失), 12.39 (br, 1H, HCl, +D2O消失)。 1 H NMR (CDCl 3 -d): δ: 1.80-1.99 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.54-2.55 (d, J = 4.8Hz, 2H, -CH 2 CH 2 N-), 2.60-2.61 (d, J = 4.8Hz, 2H, -CH 2 CH 2 N-), 2.61 (s, 6H, N (CH 3 ) 2 ), 2.57-2.70 (m, 1H,- N CH 2 CH 2 CH 2 CH 2 N-), 2.91-2.92 (m, 1H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.15-3.17 (m, 1H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.73-3.74 (m, 1H, -N CH 2 CH 2 CH 2 CH 2 N-), 4.72 (s, 1H, Ar-CH-), 7.33-7.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.68-7.70 (dd, J 1 = 2.0Hz, J 2 = 8.0Hz, 1H, Ar-H), 7.82 (d, J = 2.0Hz, 1H, Ar-H), 11.70 (br, 1H, HCl, + D 2 O disappeared), 12.39 (br, 1H, HCl, + D 2 O disappeared).

実施例 3
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピペラジン-1-イル)-プロピルアミン（VI-3）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペラジン（24mmol）、炭酸カリウム（8mmol）を加え、N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピペラジン-1-イル)-プロピルアミン（VI-3）の塩酸塩（白色固体）1.7gを得る。収率は50.2%。Mp = 257.3-258.9℃， MS(m/z): 316.2[M+1]+。 Example 3
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (piperazin-1-yl) -propylamine (VI-3) hydrochloride
N, N-dimethyl-3- (3,4-dichlorophenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operated in General Synthesis Method 4, after the reaction, piperazine (24 mmol) and potassium carbonate (8 mmol) were added, and N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (piperazin-1-yl)- 1.7 g of hydrochloride (white solid) of propylamine (VI-3) is obtained. Yield 50.2%. Mp = 257.3-258.9 ° C, MS (m / z): 316.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.98-2.03 (m, 2H, -CH 2 CH2N-), 2.65 (s, 6H, N(CH3)2), 3.00-3.04 (m, 2H, -CH2 CH 2 N-), 3.09-3.15 (m, 4H, -NCH 2 CH2N-), 3.29-3.35 (m, 4H, -NCH2 CH 2 N-), 3.78-3.80 (t, J=7.2Hz, 1H, Ar-CH-), 7.27-7.29 (dd, J1=2.0Hz, J2=6.8Hz, 1H, Ar-H), 7.54 (d, J=1.2Hz, 1H, Ar-H), 7.62-7.65 (d, J=8.4Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.98-2.03 (m, 2H, -CH 2 CH 2 N-), 2.65 (s, 6H, N (CH 3 ) 2 ), 3.00-3.04 (m, 2H, -CH 2 CH 2 N-), 3.09-3.15 (m, 4H, -N CH 2 CH 2 N-), 3.29-3.35 (m, 4H, -NCH 2 CH 2 N-), 3.78 -3.80 (t, J = 7.2Hz, 1H, Ar-CH-), 7.27-7.29 (dd, J 1 = 2.0Hz, J 2 = 6.8Hz, 1H, Ar-H), 7.54 (d, J = 1.2 Hz, 1H, Ar-H), 7.62-7.65 (d, J = 8.4 Hz, 1H, Ar-H).

実施例 4
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン（VI-4）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン（VI-4）の塩酸塩（白色固体）1.62 gを得る。収率は52.2%。Mp = 172.1-174.8℃， MS(m/z): 317.3[M+1]+。 Example 4
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine (VI-4) hydrochloride
N, N-dimethyl-3- (3,4-dichlorophenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operate in General Synthesis Method 4, and after the reaction, add morpholine (24 mmol) and potassium carbonate (8 mmol), react in General Synthesis Method 4, and then react with N, N-dimethyl-3- (3,4-dichlorophenyl) -3- 1.62 g of hydrochloride (white solid) of morpholinyl-propylamine (VI-4) is obtained. Yield 52.2%. Mp = 172.1-174.8 ° C, MS (m / z): 317.3 [M + 1] + .

1H NMR (DMSO-d6): δ: 1.98-2.42 (m, 2H, -CH 2 CH2N-), 2.30-2.40 (m, 4H, -NCH 2 CH2O), 2.70 (s, 6H, N(CH3)2), 3.01-3.08 (m, 2H, -CH2 CH 2 N-), 3.61-3.65 (m, 4H, -NCH2 CH 2 O), 3.78-3.81 (t, J=7.2Hz, 1H, Ar-CH-), 7.26-7.28 (dd, J1=2.0Hz, J2=6.8Hz, 1H, Ar-H), 7.53-7.54 (d, J=1.2Hz, 1H, Ar-H), 7.62-7.64 (d, J=8.4Hz, 1H, Ar-H), 10.49 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 1.98-2.42 (m, 2H, -CH 2 CH 2 N-), 2.30-2.40 (m, 4H, -N CH 2 CH 2 O), 2.70 (s, 6H, N (CH 3 ) 2 ), 3.01-3.08 (m, 2H, -CH 2 CH 2 N-), 3.61-3.65 (m, 4H, -NCH 2 CH 2 O), 3.78-3.81 (t, J = 7.2Hz, 1H, Ar-CH-), 7.26-7.28 (dd, J 1 = 2.0Hz, J 2 = 6.8Hz, 1H, Ar-H), 7.53-7.54 (d, J = 1.2Hz, 1H, Ar-H), 7.62-7.64 (d, J = 8.4 Hz, 1H, Ar-H), 10.49 (br, 1H, HCl, + D 2 O disappearance).

実施例 5
N-メチル-N-ベンジル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン（VI-5）塩酸塩の調製
3-クロロ-1-(3,4-ジクロロフェニル)-アセトン（0.05mol）、N-メチルベンジルアミン塩酸塩（0.05mol）、ジイソプロピルエチルアミン(0.15mol) をアセトニトリル（100mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物16.7 gを得る。収率は85.0%。MS(m/z): 322.1[M+1]+。 Example 5
Preparation of N-methyl-N-benzyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine (VI-5) hydrochloride
3-Chloro-1- (3,4-dichlorophenyl) -acetone (0.05 mol), N-methylbenzylamine hydrochloride (0.05 mol), diisopropylethylamine (0.15 mol) are dissolved in acetonitrile (100 mL). To obtain 16.7 g of a white solid product. Yield 85.0%. MS (m / z): 322.1 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.64 gを得る。収率は92.2%。MS(m/z): 324.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 3.64 g of a white solid. Yield 92.2%. MS (m / z): 324.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を入れ、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン（VI-5）の塩酸塩（白色固体）1.8 gを得る。収率は48.5%。Mp= 257.0-259.5℃， MS(m/z): 393.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine (VI-5) hydrochloride (white solid) 1.8 g Get. Yield 48.5%. Mp = 257.0-259.5 ° C, MS (m / z): 393.3 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 2.45-2.58 (m, 2H, -CH 2 CH2N-), 2.49-2.58 (m, 2H, -NCH 2 CH2O), 2.69 (s, 3H, -NCH3), 2.87-2.95 (m, 2H, -CH2 CH 2 N-), 3.08-3.15 (m, 2H, -NCH 2 CH2O), 3.73-3.79 (m, 4H, -NCH2 CH 2 O), 4.24 (s, 2H, Ar-CH2-), 4.31-4.33 (d, J=6.4Hz, 1H, Ar-CH-), 7.36-7.48 (m, 6H, Ar-H), 7.66-7.68 (d, J=8.4Hz, 1H, Ar-H), 7.77 (d, J=2.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.45-2.58 (m, 2H, -CH 2 CH 2 N-), 2.49-2.58 (m, 2H, -N CH 2 CH 2 O), 2.69 (s, 3H, -NCH 3 ), 2.87-2.95 (m, 2H, -CH 2 CH 2 N- ), 3.08-3.15 (m, 2H, -N CH 2 CH 2 O), 3.73-3.79 (m , 4H, -NCH 2 CH 2 O), 4.24 (s, 2H, Ar-CH 2- ), 4.31-4.33 (d, J = 6.4Hz, 1H, Ar-CH-), 7.36-7.48 (m, 6H , Ar-H), 7.66-7.68 (d, J = 8.4 Hz, 1H, Ar-H), 7.77 (d, J = 2.0 Hz, 1H, Ar-H).

実施例 6
4-(3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン（VI-6）塩酸塩の調製
3-クロロ-1-(3,4-ジクロロフェニル)-アセトン（0.05mol）、モルホリン（0.05mol）、ジイソプロピルエチルアミン(0.15mol) をアセトニトリル（100mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物13.2 gを得る。収率は81.7%。MS(m/z): 288.1[M+1]+。 Example 6
Preparation of 4- (3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine (VI-6) hydrochloride
Dissolve 3-chloro-1- (3,4-dichlorophenyl) -acetone (0.05 mol), morpholine (0.05 mol), and diisopropylethylamine (0.15 mol) in acetonitrile (100 mL), and operate in General Synthesis Method 2 Method B. To obtain 13.2 g of a white solid product. Yield 81.7%. MS (m / z): 288.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.04gを得る。収率は93.5%。MS(m/z): 290.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 3.04 g of a white solid. Yield 93.5%. MS (m / z): 290.2 [M + 1] < +>.

前記生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、4-(3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン（VI-6）の塩酸塩（白色固体）1.6 gを得る。収率は48.3%。Mp= 205.0-207.5℃， MS(m/z): 343.3[M+1]+。 The product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL) and operated by General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) And then reacted according to General Synthesis Method 4. Hydrochloric acid salt of 4- (3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine (VI-6) (white solid) 1.6 g Get. Yield 48.3%. Mp = 205.0-207.5 ° C, MS (m / z): 343.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ:1.92 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.60 (m, 2H, -CH 2 CH2N-), 2.91-2.94 (m, 2H, -CH2 CH 2 N-), 3.07 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 3.07 (m, 4H, -NCH 2 CH2O), 3.78 (m, 4H, -NCH2 CH 2 O), 4.43-4.46 (d, J=10.8Hz, 1H, Ar-CH-), 7.61-7.63 (d, J=8.4Hz, 1H, Ar-H), 7.71-7.73 (d, J=8.4Hz, 1H, Ar-H), 7.93(s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.92 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.60 (m, 2H, -CH 2 CH 2 N-), 2.91-2.94 (m, 2H, -CH 2 CH 2 N-), 3.07 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.07 (m, 4H, -N CH 2 CH 2 O ), 3.78 (m, 4H, -NCH 2 CH 2 O), 4.43-4.46 (d, J = 10.8Hz, 1H, Ar-CH-), 7.61-7.63 (d, J = 8.4Hz, 1H, Ar- H), 7.71-7.73 (d, J = 8.4 Hz, 1H, Ar-H), 7.93 (s, 1H, Ar-H).

実施例 7
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ピペリジニル-プロピルアミン（VI-7）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ピペリジニル-プロピルアミン（VI-7）の塩酸塩（白色固体）1.60 gを得る。収率は51.8%。Mp= 169.1-171.8℃， MS(m/z): 315.3[M+1]+。 Example 7
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3-piperidinyl-propylamine (VI-7) hydrochloride
N, N-dimethyl-3- (3,4-dichlorophenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operate according to General Synthesis Method 4, and after the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) are added and reacted according to General Synthesis Method 4. N, N-dimethyl-3- (3,4-dichlorophenyl) -3- 1.60 g of piperidinyl-propylamine (VI-7) hydrochloride (white solid) is obtained. Yield 51.8%. Mp = 169.1-171.8 ° C, MS (m / z): 315.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.65-1.70 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.09-2.12 (m, 2H, -CH 2 CH2N-), 2.69 (s, 6H, N(CH3)2), 2.95-3.00 (m, 2H, -CH2 CH 2 N-), 3.17 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.95-4.98 (d, J=9.6Hz, 1H, Ar-CH-), 7.26-7.29 (dd, J1=2.0Hz, J2=8.0Hz, 1H, Ar-H), 7.53-7.54 (d, J=1.2Hz, 1H, Ar-H), 7.61-7.64 (d, J=8.4Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.65-1.70 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.09-2.12 (m, 2H, -CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.95-3.00 (m, 2H, -CH 2 CH 2 N- ), 3.17 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.95-4.98 (d, J = 9.6Hz, 1H, Ar-CH-), 7.26-7.29 (dd, J 1 = 2.0Hz, J 2 = 8.0Hz, 1H, Ar- H), 7.53-7.54 (d, J = 1.2Hz, 1H, Ar-H), 7.61-7.64 (d, J = 8.4Hz, 1H, Ar-H).

実施例 8
N,N-ジメチル-3-(4-クロロフェニル)-3-モルホリニル-プロピルアミン（VI-8）塩酸塩の調製
4-クロロアセトフェノン(0.1mol)、ジメチルアミン塩酸塩（0.11mol）及びパラホルムアルデヒド（0.13mol）を95％エタノール（20mL）に溶かし、濃塩酸（0.2mL）を加え、一般合成法二の方法Cで操作し、白色固体19.8gを得る。収率は80.2％。MS(m/z): 212.1[M+1]+。 Example 8
Preparation of N, N-dimethyl-3- (4-chlorophenyl) -3-morpholinyl-propylamine (VI-8) hydrochloride
4-chloroacetophenone (0.1 mol), dimethylamine hydrochloride (0.11 mol) and paraformaldehyde (0.13 mol) are dissolved in 95% ethanol (20 mL) and concentrated hydrochloric acid (0.2 mL) is added. To obtain 19.8 g of a white solid. Yield 80.2%. MS (m / z): 212.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.32 gを得る。収率は93.2%。MS(m/z): 214.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.32 g of a white solid. Yield 93.2%. MS (m / z): 214.1 [M + 1] + .

前記中間体（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(4-クロロフェニル)-3-モルホリニル-プロピルアミン（VI-8）の塩酸塩（白色固体）1.43 gを得る。収率は50.5%。Mp= 131.0-134.3℃， MS(m/z): 283.2[M+1]+。 The above intermediate (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) Is added and reacted in General Synthesis Method 4 to obtain 1.43 g of hydrochloride (white solid) of N, N-dimethyl-3- (4-chlorophenyl) -3-morpholinyl-propylamine (VI-8). Yield 50.5%. Mp = 131.0-134.3 ° C, MS (m / z): 283.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.01-2.06 (m, 1H, -CH 2 CH2N-), 2.29-2.37 (m, 4H, -NCH 2 CH2O), 2.39-2.42 (m, 1H, -CH 2 CH2N-), 2.69 (s, 6H, N(CH3)2), 2.79-2.86 (m, 1H, -CH2 CH 2 N-), 3.01-3.08 (m, 1H, -CH2 CH 2 N-), 3.51-3.55 (m, 4H, -NCH2 CH 2 O), 3.57-3.60 (t, J=7.2Hz, 1H, Ar-CH-), 7.28-7.30 (d, J=8.4Hz, 2H, Ar-H), 7.41-7.43 (d, J=8.0Hz, 2H, Ar-H), 10.99 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.01-2.06 (m, 1H, -CH 2 CH 2 N-), 2.29-2.37 (m, 4H, -N CH 2 CH 2 O), 2.39-2.42 ( m, 1H, -CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.79-2.86 (m, 1H, -CH 2 CH 2 N-), 3.01-3.08 (m, 1H, -CH 2 CH 2 N-), 3.51-3.55 (m, 4H, -NCH 2 CH 2 O), 3.57-3.60 (t, J = 7.2Hz, 1H, Ar-CH-), 7.28-7.30 ( d, J = 8.4 Hz, 2H, Ar—H), 7.41-7.43 (d, J = 8.0 Hz, 2H, Ar—H), 10.99 (br, 1H, HCl, + D 2 O disappearance).

実施例 9
4-(3-(4-クロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン（VI-9）塩酸塩の調製
4-クロロアセトフェノン(20mmol)、モルホリン（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体5.2gを得る。収率は90.0％。MS(m/z): 254.2[M+1]+。 Example 9
Preparation of 4- (3- (4-chlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine (VI-9) hydrochloride
Dissolve 4-chloroacetophenone (20 mmol), morpholine (22 mmol) and paraformaldehyde (26 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.05 mL), and operate according to Method C of General Synthesis Method 2 to obtain a white solid Obtain 5.2g. Yield 90.0%. MS (m / z): 254.2 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.6gを得る。収率は89.3%。MS(m/z): 256.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 2.6 g of a white solid. Yield 89.3%. MS (m / z): 256.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、4-(3-(4-クロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン（VI-9）の塩酸塩（白色固体）1.56gを得る。収率は51.3%。Mp= 202.5-203.7℃， MS(m/z): 309.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to give 1.56 g of 4- (3- (4-chlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine (VI-9) hydrochloride (white solid) obtain. Yield 51.3%. Mp = 202.5-203.7 ° C, MS (m / z): 309.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ:1.93 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.61 (m, 2H, -CH 2 CH2N-), 2.90-2.94 (m, 2H, -CH2 CH 2 N-), 3.06 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 3.07 (m, 4H, -NCH 2 CH2O), 3.81 (m, 4H, -NCH2 CH 2 O), 4.43-4.46 (d, J=10.8Hz, 1H, Ar-CH), 7.22-7.25 (d, J=8.4Hz, 2H, Ar-H), 7.40-7.42 (d, J=8.0Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.93 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.61 (m, 2H, -CH 2 CH 2 N-), 2.90-2.94 (m, 2H, -CH 2 CH 2 N-), 3.06 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.07 (m, 4H, -N CH 2 CH 2 O ), 3.81 (m, 4H, -NCH 2 CH 2 O), 4.43-4.46 (d, J = 10.8Hz, 1H, Ar-CH), 7.22-7.25 (d, J = 8.4Hz, 2H, Ar-H ), 7.40-7.42 (d, J = 8.0 Hz, 2H, Ar-H).

実施例 10
N,N-ジメチル-3-(4-メチルフェニル)-3-モルホリニル-プロピルアミン（VI-10）塩酸塩の調製
4-メチルアセトフェノン(20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体3.76gを得る。収率は82.9％。MS(m/z): 192.1[M+1]+。 Example 10
Preparation of N, N-dimethyl-3- (4-methylphenyl) -3-morpholinyl-propylamine (VI-10) hydrochloride
Dissolve 4-methylacetophenone (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.05 mL), and operate in Method C of General Synthesis Method 2. To give 3.76 g of a white solid. Yield 82.9%. MS (m / z): 192.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.06 gを得る。収率は90.2%。MS(m/z): 194.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 2.06 g of a white solid. Yield 90.2%. MS (m / z): 194.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(4-メチルフェニル)-3-モルホリニル-プロピルアミン（VI-10）の塩酸塩（白色固体）1.34 gを得る。収率は50.0%。Mp= 234.1-236.9℃， MS(m/z): 263.2 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.34 g of hydrochloride (white solid) of N, N-dimethyl-3- (4-methylphenyl) -3-morpholinyl-propylamine (VI-10). Yield 50.0%. Mp = 234.1-236.9 ° C., MS (m / z): 263.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.35 (s, 3H, Ar-CH3), 2.62-2.64 (t, J=6.4Hz, 2H, -CH 2 CH2N-), 2.70 (s, 6H, N(CH3)2), 2.80-2.82 (t, J=6.4Hz, 2H, -CH2 CH 2 N-), 2.87-2.94 (m, 4H, -NCH 2 CH2O), 3.66-3.87 (m, 4H, -NCH2 CH 2 O), 4.51-4.53 (d, J=8.0Hz, 1H, Ar-CH-), 7.30-7.32 (d, J=8.0Hz, 2H, Ar-H), 7.57-7.59 (d, J=8.0Hz, 2H, Ar-H), 10.99 (br, 1H, HCl, +D2O消失), 12.18 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.35 (s, 3H, Ar-CH 3 ), 2.62-2.64 (t, J = 6.4Hz, 2H, -CH 2 CH 2 N-), 2.70 (s, 6H, N (CH 3 ) 2 ), 2.80-2.82 (t, J = 6.4Hz, 2H, -CH 2 CH 2 N- ), 2.87-2.94 (m, 4H, -N CH 2 CH 2 O), 3.66 -3.87 (m, 4H, -NCH 2 CH 2 O), 4.51-4.53 (d, J = 8.0Hz, 1H, Ar-CH-), 7.30-7.32 (d, J = 8.0Hz, 2H, Ar-H ), 7.57-7.59 (d, J = 8.0 Hz, 2H, Ar—H), 10.99 (br, 1H, HCl, + D 2 O disappearance), 12.18 (br, 1H, HCl, + D 2 O disappearance).

実施例 11
4-(3-(4-メチルピペラジン-1-イル)-1-(4-メチルフェニル)プロピル)モルホリン（VI-11）塩酸塩の調製
4-メチルアセトフェノン(20mmol)、1-メチルピペラジン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.50gを得る。収率は79.8％。MS(m/z): 247.1[M+1]+。 Example 11
Preparation of 4- (3- (4-methylpiperazin-1-yl) -1- (4-methylphenyl) propyl) morpholine (VI-11) hydrochloride
Dissolve 4-methylacetophenone (20 mmol), 1-methylpiperazine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.05 mL), and use General Synthesis Method 2 Method C. Operate to obtain 4.50 g of white solid. Yield 79.8%. MS (m / z): 247.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.68gを得る。収率は94.4%。MS(m/z): 279.2[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.68 g of a white solid. Yield 94.4%. MS (m / z): 279.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、4-(3-(4-メチルピペラジン-1-イル)-1-(4-メチルフェニル)プロピル)モルホリン（VI-11）の塩酸塩（白色固体）1.43gを得る。収率は46.0%。MS(m/z): 318.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to give 4- (3- (4-methylpiperazin-1-yl) -1- (4-methylphenyl) propyl) morpholine (VI-11) hydrochloride (white solid ) Obtain 1.43g. Yield 46.0%. MS (m / z): 318.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.02-2.05 (m, 2H, -CHCH 2 CH2N-), 2.20 (s, 3H, -NCH3), 2.33 (m, 8H, -NCH 2 CH 2 N-), 2.35 (s, 3H, Ar-CH3), 2.82-2.89 (m, 2H, -CHCH2 CH 2 N-), 3.08-3.16 (m, 2H, -NCH 2 CH2O), 3.63-3.75(m, 4H, -NCH2 CH 2 O), 4.28 (s, 2H, Ar-CH2-), 4.33-4.35 (t, J=7.2Hz, 1H, Ar-CH-), 7.31-7.45 (m, 7H, Ar-H), 7.73 (d, J=2.0Hz, 1H, Ar-H), 10.98 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.02-2.05 (m, 2H, -CH CH 2 CH 2 N-), 2.20 (s, 3H, -NCH 3 ), 2.33 (m, 8H, -N CH 2 CH 2 N-), 2.35 (s, 3H, Ar-CH 3 ), 2.82-2.89 (m, 2H, -CHCH 2 CH 2 N-), 3.08-3.16 (m, 2H, -N CH 2 CH 2 O), 3.63-3.75 (m, 4H, -NCH 2 CH 2 O), 4.28 (s, 2H, Ar-CH 2- ), 4.33-4.35 (t, J = 7.2Hz, 1H, Ar-CH-) , 7.31-7.45 (m, 7H, Ar -H), 7.73 (d, J = 2.0Hz, 1H, Ar-H), 10.98 (br, 1H, HCl, + D 2 O disappeared).

実施例 12
4-(3-(4-メチルフェニル)-3-(モルホリニル)プロピル)ピロール（VI-12）塩酸塩の調製
4-メチルアセトフェノン(20mmol)、ピロリジン（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.40gを得る。収率は87.0％。MS(m/z): 218.1[M+1]+。 Example 12
Preparation of 4- (3- (4-methylphenyl) -3- (morpholinyl) propyl) pyrrole (VI-12) hydrochloride
4-Methylacetophenone (20mmol), pyrrolidine (22mmol) and paraformaldehyde (26mmol) are dissolved in 95% ethanol (10mL), concentrated hydrochloric acid (0.05mL) is added, and it is operated by Method C of General Synthetic Method II. 4.40g is obtained. Yield 87.0%. MS (m / z): 218.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.25gを得る。収率は88.2%。MS(m/z): 220.2[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.25 g of a white solid. Yield 88.2%. MS (m / z): 220.2 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、4-(3-(4-メチルフェニル)-3-(モルホリニル)プロピル)ピロール（VI-12）の塩酸塩（白色固体）1.45gを得る。収率は50.3%。MS(m/z): 289.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.45 g of 4- (3- (4-methylphenyl) -3- (morpholinyl) propyl) pyrrole (VI-12) hydrochloride (white solid). Yield 50.3%. MS (m / z): 289.2 [M + 1] + .

1H NMR (DMSO-d6)＋D2O: δ: 1.89 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.62-2.70 (m, 2H, -CHCH 2 CH2N-), 2.35 (s, 3H, Ar-CH3), 3.13 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 3.15 (m, 2H, -CHCH2 CH 2 N-), 3.30-2.41 (m, 4H, -NCH 2 CH2O), 3.56-3.65 (m, 4H, -NCH2 CH 2 O), 3.77-3.79 (t, J=7.2Hz, 1H, Ar-CH-), 7.35-7.38 (d, J=8.0Hz, 2H, Ar-H), 7.42-7.44 (d, J=8.0Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.89 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.62-2.70 (m, 2H, -CH CH 2 CH 2 N- ), 2.35 (s, 3H, Ar-CH 3 ), 3.13 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.15 (m, 2H, -CHCH 2 CH 2 N-), 3.30 -2.41 (m, 4H, -N CH 2 CH 2 O), 3.56-3.65 (m, 4H, -NCH 2 CH 2 O), 3.77-3.79 (t, J = 7.2Hz, 1H, Ar-CH-) 7.35-7.38 (d, J = 8.0Hz, 2H, Ar-H), 7.42-7.44 (d, J = 8.0Hz, 2H, Ar-H).

実施例 13
N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-13）塩酸塩の調製
ベンゾチオフェン（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、,3-クロロプロピオン酸クロライド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、3-クロロ-1-(ベンゾチオフェン-3-イル)-アセトン 9.6 g（白色固体）を得る。収率は85.3%。MS(m/z): 225.0[M+1]+。 Example 13
Preparation of N, N-dimethyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-13) hydrochloride Benzothiophene (0.05 mol) in dichloromethane (30 mL) Dissolve and control the internal temperature to 5 ° C or lower, add AlCl 3 (0.10 mol) in portions, add 3-chloropropionic acid chloride (0.055 mol) dropwise, and operate according to Method A in General Synthesis Method 3 9.6 g (white solid) of -chloro-1- (benzothiophen-3-yl) -acetone are obtained. Yield 85.3%. MS (m / z): 225.0 [M + 1] + .

該中間体（0.03mol）、ジメチルアミン水溶液（0.15mol）を無水エタノール（50mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物6.5 gを得る。収率は80.3%。MS(m/z): 234.1[M+1]+。 The intermediate (0.03 mol) and dimethylamine aqueous solution (0.15 mol) are dissolved in absolute ethanol (50 mL) and operated by Method A of General Synthesis Method 2 to obtain 6.5 g of a white solid product. Yield 80.3%. MS (m / z): 234.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、，白色固体2.45 gを得る。収率は90.5%。MS(m/z): 236.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 2.45 g of a white solid. Yield 90.5%. MS (m / z): 236.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-13）の塩酸塩（白色固体）1.24 gを得る。収率は43.2%。Mp= 259.7-262.2℃， MS(m/z): 289.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) ), And the reaction is carried out according to General Synthesis Method 4. The hydrochloride salt of N, N-dimethyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-13) ( White solid) 1.24 g is obtained. Yield 43.2%. Mp = 259.7-262.2 ° C, MS (m / z): 289.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.91 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.62-2.70 (m, 2H, -CH 2 CH2N-), 2.73 (s, 6H, N(CH3)2), 2.97-3.02 (m, 2H, -CH2 CH 2 N-), 3.12 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 4.98-5.01 (d, J=9.6Hz, 1H, Ar-CH-), 7.44-7.52 (m, 2H, Ar-H), 8.05-8.08 (t, J=8.4Hz, 2H, Ar-H), 8.22 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.91 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.62-2.70 (m, 2H, -CH 2 CH 2 N- ), 2.73 (s, 6H, N (CH 3 ) 2 ), 2.97-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.12 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N -), 4.98-5.01 (d, J = 9.6Hz, 1H, Ar-CH-), 7.44-7.52 (m, 2H, Ar-H), 8.05-8.08 (t, J = 8.4Hz, 2H, Ar- H), 8.22 (s, 1H, Ar-H).

実施例 14
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-14）塩酸塩の調製
3-クロロ-1-(ベンゾチオフェン-3-イル)-アセトン（0.05mol）、N-メチルベンジルアミン塩酸塩（0.05mol）、ジイソプロピルエチルアミン(0.15mol) をアセトニトリル（100mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物14.4 gを得る。収率は83.5%。MS(m/z): 310.2[M+1]+。 Example 14
Preparation of N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-14) hydrochloride
3-chloro-1- (benzothiophen-3-yl) -acetone (0.05 mol), N-methylbenzylamine hydrochloride (0.05 mol), diisopropylethylamine (0.15 mol) dissolved in acetonitrile (100 mL), general synthesis method Operate in the second method B to obtain 14.4 g of a white solid product. Yield 83.5%. MS (m / z): 310.2 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.12 gを得る。収率は90.0%。MS(m/z): 312.2[M+1]+。 The intermediate (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 3.12 g of a white solid. Yield 90.0%. MS (m / z): 312.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-14）の塩酸塩（白色固体）1.83gを得る。収率は52.5%。Mp= 297.0-299.5℃， MS(m/z): 365.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-14) hydrochloric acid 1.83 g of salt (white solid) are obtained. Yield 52.5%. Mp = 297.0-299.5 ° C, MS (m / z): 365.3 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.93 (m, 4H, -NCH2 CH 2 CH 2 CH2N-),2.58-2.68 (m, 2H, -CH 2 CH2N-), 2.73 (s, 3H, -NCH3), 2.92-2.97 (m, 2H, -CH2 CH 2 N-), 3.15 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 4.25 (s, 2H, Ar-CH2-), 4.58-4.60 (d, J=7.6Hz, 1H, Ar-CH-), 7.33-7.42 (m, 5H, Ar-H), 7.44-7.53 (m, 2H, Ar-H), 8.06-8.09 (t, J=8.4Hz, 2H, Ar-H), 8.24 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.93 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.58-2.68 (m, 2H, -CH 2 CH 2 N- ), 2.73 (s, 3H, -NCH 3 ), 2.92-2.97 (m, 2H, -CH 2 CH 2 N-), 3.15 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 4.25 (s, 2H, Ar-CH 2- ), 4.58-4.60 (d, J = 7.6Hz, 1H, Ar-CH-), 7.33-7.42 (m, 5H, Ar-H), 7.44-7.53 (m , 2H, Ar-H), 8.06-8.09 (t, J = 8.4 Hz, 2H, Ar-H), 8.24 (s, 1H, Ar-H).

実施例 15
N-メチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-15）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-15）の塩酸塩1.18gを得る。収率は68.4%。Mp= 189.3-192.0℃， MS(m/z): 275.2[M+1]+。 Example 15
Preparation of N-methyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-15) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) in methanol (30 mL) Dissolve in, add hydrogen at room temperature and normal pressure, react for 2 hours, remove palladium on carbon by filtration, concentrate the filtrate, and obtain a white solid. After recrystallization from absolute ethanol (10 mL), 1.18 g of hydrochloride of N-methyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-15) is obtained. Yield 68.4%. Mp = 189.3-192.0 ° C, MS (m / z): 275.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.85 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.58-2.67 (m, 2H, -CH 2 CH2N-), 2.95-3.00 (m, 2H, -CH2 CH 2 N-), 3.15 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 3.45 (s, 3H, N-CH3), 4.97-5.00 (d, J=9.6Hz, 1H, Ar-CH-), 7.42-7.48 (m, 2H, Ar-H), 8.02-8.05 (t, J=8.4Hz, 2H, Ar-H), 8.25 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.85 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.58-2.67 (m, 2H, -CH 2 CH 2 N- ), 2.95-3.00 (m, 2H, -CH 2 CH 2 N- ), 3.15 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.45 (s, 3H, N-CH 3 ) , 4.97-5.00 (d, J = 9.6Hz, 1H, Ar-CH-), 7.42-7.48 (m, 2H, Ar-H), 8.02-8.05 (t, J = 8.4Hz, 2H, Ar-H) , 8.25 (s, 1H, Ar-H).

実施例 16
N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン(VI-16)塩酸塩の調製
N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン(VI-16)の塩酸塩（白色固体）1.65 gを得る。収率は55.3%。Mp= 265.3-267.0℃， MS(m/z): 303.3[M+1]+。 Example 16
Preparation of N, N-dimethyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine (VI-16) hydrochloride
N, N-dimethyl-3- (benzothiophen-3-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL). After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added and reacted according to General Synthesis Method 4. N, N-dimethyl-3- (benzothiophen-3-yl)- 1.65 g of hydrochloride (white solid) of 3-piperidinyl-propylamine (VI-16) is obtained. Yield 55.3%. Mp = 265.3-267.0 ° C, MS (m / z): 303.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.65-1.72 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.08-2.12 (m, 2H, -CH 2 CH2N-), 2.69 (s, 6H, N(CH3)2), 2.95-3.00(m, 2H, -CH2 CH 2 N-), 3.15 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.95-4.98 (d, J=9.6Hz, 1H, Ar-CH-), 7.42-7.48 (m, 2H, Ar-H), 8.03-8.05 (t, J=8.4Hz, 2H, Ar-H), 8.24 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.65-1.72 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.08-2.12 (m, 2H, -CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.95-3.00 (m, 2H, -CH 2 CH 2 N- ), 3.15 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.95-4.98 (d, J = 9.6Hz, 1H, Ar-CH-), 7.42-7.48 (m, 2H, Ar-H), 8.03-8.05 (t, J = 8.4 Hz, 2H, Ar-H), 8.24 (s, 1H, Ar-H).

実施例 17
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン（VI-17）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン（VI-17）の塩酸塩（白色固体）2.07gを得る。収率は57.4%。Mp= 312.0-313.5℃， MS(m/z): 379.3[M+1]+。 Example 17
Preparation of N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine (VI-17) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) in acetonitrile (30 mL) After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added and reacted according to General Synthesis Method 4. N-methyl-N-benzyl-3- (benzothiophene-3 Obtain 2.07 g of hydrochloride (white solid) of -yl) -3-piperidinyl-propylamine (VI-17). Yield 57.4%. Mp = 312.0-313.5 ° C, MS (m / z): 379.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.66-1.74 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.13-2.18 (m, 2H, -CH 2 CH2N-), 2.70 (s, 3H, -NCH3), 2.95-3.02 (m, 2H, -CH2 CH 2 N-), 3.17 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.26 (s, 2H, Ar-CH2-), 4.58-4.60 (d, J=6.4Hz, 1H, Ar-CH-), 7.30-7.41 (m, 5H, Ar-H), 7.42-7.51 (m, 2H, Ar-H), 8.07-8.10 (t, J=8.4Hz, 2H, Ar-H), 8.27 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.66-1.74 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.13-2.18 (m, 2H, -CH 2 CH 2 N-), 2.70 (s, 3H, -NCH 3 ), 2.95-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.17 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.26 (s, 2H, Ar-CH 2- ), 4.58-4.60 (d, J = 6.4Hz, 1H, Ar-CH-), 7.30-7.41 (m, 5H, Ar-H) 7.42-7.51 (m, 2H, Ar-H), 8.07-8.10 (t, J = 8.4 Hz, 2H, Ar-H), 8.27 (s, 1H, Ar-H).

実施例 18
N-メチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン（VI-18）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン（VI-18）の塩酸塩1.26gを得る。収率は70.0%。Mp= 193.2-195.0℃， MS(m/z): 289.1[M+1]+。 Example 18
Preparation of N-methyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine (VI-18) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) dissolved in methanol (30 mL) at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 1.26 g of N-methyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine (VI-18) hydrochloride is obtained. Yield 70.0%. Mp = 193.2-195.0 ° C, MS (m / z): 289.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.60-1.72 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.56-2.62 (m, 2H, -CH 2 CH2N-), 2.97-3.02 (m, 2H, -CH2 CH 2 N-), 3.16 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 3.46 (s, 3H, N-CH3), 4.92-4.95 (d, J=9.6Hz, 1H, Ar-CH-), 7.40-7.46 (m, 2H, Ar-H), 8.00-8.03 (t, J=8.4Hz, 2H, Ar-H), 8.23 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.60-1.72 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.56-2.62 (m, 2H, -CH 2 CH 2 N-), 2.97-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.16 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 3.46 (s, 3H , N-CH 3 ), 4.92-4.95 (d, J = 9.6Hz, 1H, Ar-CH-), 7.40-7.46 (m, 2H, Ar-H), 8.00-8.03 (t, J = 8.4Hz, 2H, Ar-H), 8.23 (s, 1H, Ar-H).

実施例 19
N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-19）塩酸塩の調製
2-アセチルベンゾチオフェン (20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.34gを得る。収率は80.6％。MS(m/z): 234.1[M+1]+。 Example 19
Preparation of N, N-dimethyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-19) hydrochloride
2-acetylbenzothiophene (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL), concentrated hydrochloric acid (0.05 mL) is added, and the procedure is performed according to Method C of General Synthesis Method 2. To obtain 4.34 g of a white solid. Yield 80.6%. MS (m / z): 234.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.57gを得る。収率は95.0%。MS(m/z): 236.1[M+1]+。 The intermediate (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.57 g of a white solid. Yield 95.0%. MS (m / z): 236.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-19）の塩酸塩（白色固体）1.31 gを得る。収率は45.6%。Mp= 255.0-257.2℃，MS(m/z): 289.2 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) ), And the reaction is carried out according to General Synthesis Method 4. The hydrochloride of N, N-dimethyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-19) ( White solid) 1.31 g is obtained. Yield 45.6%. Mp = 255.0-257.2 ° C, MS (m / z): 289.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.93 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.52-2.60 (m, 2H, -CH 2 CH2N-), 2.75 (s, 6H, -NCH3), 2.76 (m, 2H, -NCH 2 CH2CH2 CH 2 N-), 3.05-3.11 (m, 2H, -CH2 CH 2 N-), 3.20 (m, 2H, -NCH 2 CH2CH2 CH 2 N-), 4.96-5.00 (dd, J1=3.2Hz, J1=11.2Hz, 1H, Ar-CH-), 7.41-7.45 (m, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 7.88-7.90 (m, 1H, Ar-H), 7.99-8.02 (m, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.93 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.52-2.60 (m, 2H, -CH 2 CH 2 N- ), 2.75 (s, 6H, -NCH 3 ), 2.76 (m, 2H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.05-3.11 (m, 2H, -CH 2 CH 2 N-), 3.20 (m, 2H, -N CH 2 CH 2 CH 2 CH 2 N-), 4.96-5.00 (dd, J 1 = 3.2Hz, J 1 = 11.2Hz, 1H, Ar-CH-), 7.41-7.45 ( m, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 7.88-7.90 (m, 1H, Ar-H), 7.99-8.02 (m, 1H, Ar-H).

実施例 20
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-20）塩酸塩の調製
2-アセチルベンゾチオフェン(20mmol)、N-メチルベンジルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体5.33gを得る。収率は70.0％。MS(m/z): 310.1[M+1]+。 Example 20
Preparation of N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-20) hydrochloride
2-acetylbenzothiophene (20 mmol), N-methylbenzylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL) and concentrated hydrochloric acid (0.05 mL) is added. Operate with C to give 5.33 g of white solid. Yield is 70.0%. MS (m / z): 310.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.52gを得る。収率は92.0%。MS(m/z): 312.1[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 3.52 g of a white solid. Yield 92.0%. MS (m / z): 312.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-20）の塩酸塩（白色固体）1.40 gを得る。収率は40.0%。Mp= 287.5-289.2℃，MS(m/z): 365.3 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-20) hydrochloric acid 1.40 g of salt (white solid) are obtained. Yield 40.0%. Mp = 287.5-289.2 ° C, MS (m / z): 365.3 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.90 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.56-2.64(m, 2H, -CH 2 CH2N-), 2.71 (s, 3H, -NCH3), 2.90-2.95 (m, 2H, -CH2 CH 2 N-), 3.14 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 4.23 (s, 2H, Ar-CH2-), 4.56-4.58 (d, J=6.4Hz, 1H, Ar-CH-), 7.25-7.32 (m, 5H, Ar-H), 7.36 (s, 1H, Ar-H), 7.45-7.54 (m, 2H, Ar-H), 8.07-8.10 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.90 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.56-2.64 (m, 2H, -CH 2 CH 2 N- ), 2.71 (s, 3H, -NCH 3 ), 2.90-2.95 (m, 2H, -CH 2 CH 2 N- ), 3.14 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 4.23 (s, 2H, Ar-CH 2- ), 4.56-4.58 (d, J = 6.4Hz, 1H, Ar-CH-), 7.25-7.32 (m, 5H, Ar-H), 7.36 (s, 1H , Ar-H), 7.45-7.54 (m, 2H, Ar-H), 8.07-8.10 (t, J = 8.4 Hz, 2H, Ar-H).

実施例 21
N-メチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-21）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-21）の塩酸塩1.05gを得る。収率は60.5%。Mp= 175.0-176.8℃， MS(m/z): 275.3[M+1]+。 Example 21
Preparation of N-methyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-21) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) in methanol (30 mL) Dissolve in, add hydrogen at room temperature and normal pressure, react for 2 hours, remove palladium on carbon by filtration, concentrate the filtrate, and obtain a white solid. After recrystallization of absolute ethanol (10 mL), 1.05 g of hydrochloride of N-methyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-21) is obtained. Yield 60.5%. Mp = 175.0-176.8 ° C, MS (m / z): 275.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.83-1.85 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.62-2.69 (m, 2H, -CH 2 CH2N-), 2.96-3.02 (m, 2H, -CH2 CH 2 N-), 3.15-3.19 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 3.43 (s, 3H, N-CH3), 4.98-5.00 (d, J=9.6Hz, 1H, Ar-CH-), 7.25(s, 1H, Ar-H)，7.45-7.49 (m, 2H, Ar-H), 7.95-7.97 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.83-1.85 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.62-2.69 (m, 2H, -CH 2 CH 2 N-), 2.96-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.15-3.19 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 3.43 (s, 3H, N -CH 3 ), 4.98-5.00 (d, J = 9.6Hz, 1H, Ar-CH-), 7.25 (s, 1H, Ar-H), 7.45-7.49 (m, 2H, Ar-H), 7.95- 7.97 (t, J = 8.4Hz, 2H, Ar-H).

実施例 22
N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン（VI-22）塩酸塩の調製
N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン（VI-22）の塩酸塩（白色固体）1.50gを得る。収率は50.2%。Mp= 256.2-258.0℃， MS(m/z): 303.2[M+1]+。 Example 22
Preparation of N, N-dimethyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine (VI-22) hydrochloride
N, N-dimethyl-3- (benzothiophen-2-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL). After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added and reacted according to General Synthesis Method 4. N, N-dimethyl-3- (benzothiophen-2-yl)- 1.50 g of hydrochloride (white solid) of 3-piperidinyl-propylamine (VI-22) is obtained. Yield 50.2%. Mp = 256.2-258.0 ° C, MS (m / z): 303.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.58-1.65 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.02-2.09 (m, 2H, -CH 2 CH2N-), 2.72 (s, 6H, N(CH3)2), 2.95-3.02(m, 2H, -CH2 CH 2 N-), 3.13-3.16 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.96-4.99 (d, J=9.6Hz, 1H, Ar-CH-), 7.23(s, 1H, Ar-H)，7.42-7.48 (m, 2H, Ar-H), 8.03-8.05 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.58-1.65 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.02-2.09 (m, 2H, -CH 2 CH 2 N-), 2.72 (s, 6H, N (CH 3 ) 2 ), 2.95-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.13-3.16 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.96-4.99 (d, J = 9.6Hz, 1H, Ar-CH-), 7.23 (s, 1H, Ar-H), 7.42-7.48 (m, 2H, Ar -H), 8.03-8.05 (t, J = 8.4 Hz, 2H, Ar-H).

実施例 23
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン（VI-23）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ピペリジン-イル-プロピルアミン（VI-23）の塩酸塩（白色固体）1.65gを得る。収率は45.9%。Mp= 298.5 -300.0℃， MS(m/z): 379.2[M+1]+。 Example 23
Preparation of N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine (VI-23) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) in acetonitrile (30 mL) After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added and reacted according to General Synthesis Method 4. N-methyl-N-benzyl-3- (benzothiophene-2 1.65 g of hydrochloride (white solid) of -yl) -3-piperidin-yl-propylamine (VI-23) are obtained. Yield 45.9%. Mp = 298.5 -300.0 ° C, MS (m / z): 379.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.62-1.70 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.15-2.19 (m, 2H, -CH 2 CH2N-), 2.71 (s, 3H, -NCH3), 2.98-3.04 (m, 2H, -CH2 CH 2 N-), 3.13-3.16 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.27 (s, 2H, Ar-CH2-), 4.58-4.60 (d, J=6.4Hz, 1H, Ar-CH-), 7.25(s, 1H, Ar-H), 7.30-7.41 (m, 5H, Ar-H), 7.42-7.51 (m, 2H, Ar-H), 8.07-8.10 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.62-1.70 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.15-2.19 (m, 2H, -CH 2 CH 2 N-), 2.71 (s, 3H, -NCH 3 ), 2.98-3.04 (m, 2H, -CH 2 CH 2 N- ), 3.13-3.16 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.27 (s, 2H, Ar-CH 2- ), 4.58-4.60 (d, J = 6.4Hz, 1H, Ar-CH-), 7.25 (s, 1H, Ar-H) , 7.30-7.41 (m, 5H, Ar-H), 7.42-7.51 (m, 2H, Ar-H), 8.07-8.10 (t, J = 8.4Hz, 2H, Ar-H).

実施例 24
N-メチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン（VI-24）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン（VI-24）の塩酸塩1.27gを得る。収率は70.5%。Mp= 185.3-187.0℃， MS(m/z): 289.0[M+1]+。 Example 24
Preparation of N-methyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine (VI-24) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) dissolved in methanol (30 mL) at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 1.27 g of N-methyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine (VI-24) hydrochloride is obtained. Yield 70.5%. Mp = 185.3-187.0 ° C, MS (m / z): 289.0 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.62-1.73 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.54-2.59 (m, 2H, -CH 2 CH2N-), 2.97-3.03 (m, 2H, -CH2 CH 2 N-), 3.16-3.19 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 3.47 (s, 3H, N-CH3), 4.92-4.94 (d, J=9.6Hz, 1H, Ar-CH-), 7.25(s, 1H, Ar-H), 7.42-7.45 (m, 2H, Ar-H), 8.03-8.06 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.62-1.73 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.54-2.59 (m, 2H, -CH 2 CH 2 N-), 2.97-3.03 (m, 2H, -CH 2 CH 2 N- ), 3.16-3.19 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 3.47 (s , 3H, N-CH 3 ), 4.92-4.94 (d, J = 9.6Hz, 1H, Ar-CH-), 7.25 (s, 1H, Ar-H), 7.42-7.45 (m, 2H, Ar-H ), 8.03-8.06 (t, J = 8.4 Hz, 2H, Ar-H).

実施例 25
N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-25）塩酸塩の調製
N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-25）の塩酸塩（白色固体）1.38gを得る。収率は45.9%。Mp= 220.8-223.9℃， MS(m/z): 305.3[M+1]+。 Example 25
Preparation of N, N-dimethyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine (VI-25) hydrochloride
N, N-dimethyl-3- (benzothiophen-2-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL). , Operated by General Synthesis Method 4, and after the reaction, morpholine (24 mmol) and potassium carbonate (8 mmol) were added and reacted by General Synthesis Method 4, and N, N-dimethyl-3- (benzothiophen-2-yl)- 1.38 g of hydrochloride (white solid) of 3-morpholinyl-propylamine (VI-25) is obtained. Yield 45.9%. Mp = 220.8-223.9 ° C, MS (m / z): 305.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.49-2.51 (m, 1H, -CH 2 CH2N-), 2.75 (s, 6H, N(CH3)2), 2.75-2.83 (m, 2H, -CH2 CH 2 N-), 3.07 (m, 1H, -CH 2 CH2-), 3.07-3.28 (m, 4H, -NCH 2 CH2O), 3.85-3.92 (m, 4H, -NCH2 CH 2 O), 4.95-4.98 (dd, J1=2.4Hz, J2=11.2Hz, 1H, Ar-CH-), 7.43-7.47 (m, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 7.90-7.93 (m, 1H, Ar-H), 8.00-8.03 (m, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.49-2.51 (m, 1H, -CH 2 CH 2 N-), 2.75 (s, 6H, N (CH 3 ) 2 ), 2.75-2.83 (m, 2H, -CH 2 CH 2 N- ), 3.07 (m, 1H, -CH 2 CH 2- ), 3.07-3.28 (m, 4H, -N CH 2 CH 2 O), 3.85-3.92 (m , 4H, -NCH 2 CH 2 O), 4.95-4.98 (dd, J 1 = 2.4Hz, J 2 = 11.2Hz, 1H, Ar-CH-), 7.43-7.47 (m, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 7.90-7.93 (m, 1H, Ar-H), 8.00-8.03 (m, 1H, Ar-H).

実施例 26
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-26）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-26）の塩酸塩（白色固体）1.56gを得る。収率は43.2%。Mp= 312.2 -314.0℃， MS(m/z): 381.2[M+1]+。 Example 26
Preparation of N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine (VI-26) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) in acetonitrile (30 mL) After the reaction, add morpholine (24 mmol) and potassium carbonate (8 mmol), and react with General Synthesis Method 4. N-methyl-N-benzyl-3- (benzothiophene-2 1.56 g of hydrochloride (white solid) of -yl) -3-morpholinyl-propylamine (VI-26) are obtained. Yield 43.2%. Mp = 312.2-314.0 ° C., MS (m / z): 381.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.67 (s, 3H, -NCH3), 2.78-2.93 (m, 2H, -CH 2 CH2N-), 2.98-3.16 (m, 4H, -NCH 2 CH2O), 3.79-3.81 (m, 2H, -CH2 CH 2 N-), 3.91-4.02 (m, 4H, -NCH2 CH 2 O), 4.23-4.31 (m, 2H, Ar-CH2-), 5.03 (s, 1H, Ar-CH-), 7.32-7.35 (m, 3H, Ar-H), 7.40-7.46 (m, 2H, Ar-H), 7.56-7.58 (m, 2H, Ar-H), 7.75 (s, 1H, Ar-H), 7.87-7.90 (m, 1H, Ar-H), 7.99-8.02 (m, 1H, Ar-H), 9.56 (br, 1H, HCl, +D2O消失), 11.38 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.67 (s, 3H, -NCH 3 ), 2.78-2.93 (m, 2H, -CH 2 CH 2 N-), 2.98-3.16 (m, 4H, -N CH 2 CH 2 O), 3.79-3.81 (m, 2H, -CH 2 CH 2 N-), 3.91-4.02 (m, 4H, -NCH 2 CH 2 O), 4.23-4.31 (m, 2H, Ar- CH 2- ), 5.03 (s, 1H, Ar-CH-), 7.32-7.35 (m, 3H, Ar-H), 7.40-7.46 (m, 2H, Ar-H), 7.56-7.58 (m, 2H , Ar-H), 7.75 (s, 1H, Ar-H), 7.87-7.90 (m, 1H, Ar-H), 7.99-8.02 (m, 1H, Ar-H), 9.56 (br, 1H, HCl , + D 2 O disappeared), 11.38 (br, 1H, HCl, + D 2 O disappeared).

実施例 27
N-メチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-27）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-27）の塩酸塩1.18gを得る。収率は65.3%。Mp= 192.3-194.6℃， MS(m/z): 291.1[M+1]+。 Example 27
Preparation of N-methyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine (VI-27) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) dissolved in methanol (30 mL) at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 1.18 g of hydrochloride of N-methyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine (VI-27) is obtained. Yield 65.3%. Mp = 192.3-194.6 ° C, MS (m / z): 291.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.51-2.53 (m, 2H, -CH 2 CH2N-), 2.97-3.03 (m, 2H, -CH2 CH 2 N-), 3.07-3.28 (m, 4H, -NCH 2 CH2O), 3.45 (s, 3H, N-CH3), 3.87-3.92 (m, 4H, -NCH2 CH 2 O), 4.93-4.95 (d, J=9.6Hz, 1H, Ar-CH-), 7.23(s, 1H, Ar-H), 7.42-7.44 (m, 2H, Ar-H), 8.02-8.05 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.51-2.53 (m, 2H, -CH 2 CH 2 N-), 2.97-3.03 (m, 2H, -CH 2 CH 2 N- ), 3.07-3.28 (m, 4H, -N CH 2 CH 2 O), 3.45 (s, 3H, N-CH 3 ), 3.87-3.92 (m, 4H, -NCH 2 CH 2 O), 4.93-4.95 (d , J = 9.6Hz, 1H, Ar-CH-), 7.23 (s, 1H, Ar-H), 7.42-7.44 (m, 2H, Ar-H), 8.02-8.05 (t, J = 8.4Hz, 2H , Ar-H).

実施例 28
N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン（VI-28）塩酸塩の調製
N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン（VI-28）の塩酸塩（白色固体）1.41gを得る。収率は46.8%。Mp= 228.9-231.6℃，MS(m/z): 305.3[M+1]+。 Example 28
Preparation of N, N-dimethyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine (VI-28) hydrochloride
N, N-dimethyl-3- (benzothiophen-3-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL). , Operated by General Synthesis Method 4, and after the reaction, morpholine (24 mmol) and potassium carbonate (8 mmol) were added and reacted by General Synthesis Method 4, and N, N-dimethyl-3- (benzothiophen-3-yl)- 1.41 g of hydrochloride (white solid) of 3-morpholinyl-propylamine (VI-28) is obtained. Yield 46.8%. Mp = 228.9-231.6 ° C, MS (m / z): 305.3 [M + 1] + .

1H NMR (CDCl3-d): δ: 2.82-2.85 (m, 2H, -CH 2 CH2N-), 2.87-2.91 (m, 2H, -CH2 CH 2 N-), 2.87-3.01 (m, 2H, -NCH 2 CH2O), 3.26-3.30 (br, 6H, N(CH3)2), 3.86-3.89 (m, 2H, -NCH 2 CH2O), 3.99-4.05 (m, 2H, -NCH2 CH 2 O), 4.11-4.17 (m, 1H, -NCH2 CH 2 O), 4.28-4.34 (m, 1H, -NCH2 CH 2 O), 5.48-5.50 (d, J=6.4Hz, 1H, Ar-CH-), 7.44-7.63 (m, 2H, Ar-H), 7.87-7.99 (m, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 8.62 (s, 1H, Ar-H), 11.92 (br, 1H, HCl, +D2O消失), 12.61 (br, 1H, HCl, +D2O消失)。 1 H NMR (CDCl 3 -d): δ: 2.82-2.85 (m, 2H, -CH 2 CH 2 N-), 2.87-2.91 (m, 2H, -CH 2 CH 2 N- ), 2.87-3.01 ( m, 2H, -N CH 2 CH 2 O), 3.26-3.30 (br, 6H, N (CH 3 ) 2 ), 3.86-3.89 (m, 2H, -N CH 2 CH 2 O), 3.99-4.05 ( m, 2H, -NCH 2 CH 2 O), 4.11-4.17 (m, 1H, -NCH 2 CH 2 O), 4.28-4.34 (m, 1H, -NCH 2 CH 2 O), 5.48-5.50 (d, J = 6.4Hz, 1H, Ar-CH-), 7.44-7.63 (m, 2H, Ar-H), 7.87-7.99 (m, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 8.62 (s, 1H, Ar-H), 11.92 (br, 1H, HCl, + D 2 O disappearance), 12.61 (br, 1H, HCl, + D 2 O disappearance).

実施例 29
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン（VI-29）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン（VI-29）の塩酸塩（白色固体）1.85gを得る。収率は51.2%。Mp= 320.5 -323.0℃， MS(m/z): 381.2[M+1]+。 Example 29
Preparation of N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine (VI-29) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) in acetonitrile (30 mL) After the reaction, add morpholine (24 mmol) and potassium carbonate (8 mmol), and react with General Synthesis Method 4. N-methyl-N-benzyl-3- (benzothiophene-3 1.85 g of hydrochloride (white solid) of -yl) -3-morpholinyl-propylamine (VI-29) are obtained. Yield 51.2%. Mp = 320.5-323.0 ° C, MS (m / z): 381.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.65 (s, 3H, -NCH3), 2.75-2.56 (m, 2H, -CH 2 CH2N-), 2.97-3.13(m, 4H, -NCH 2 CH2O), 3.75-3.80 (m, 2H, -CH2 CH 2 N-), 3.92-4.03 (m, 4H, -NCH2 CH 2 O), 4.25-4.31 (m, 2H, Ar-CH2-), 5.05 (s, 1H, Ar-CH-), 7.30-7.33 (m, 3H, Ar-H), 7.38-7.44 (m, 2H, Ar-H), 7.49 (s, 1H, Ar-H), 7.59-7.64 (m, 2H, Ar-H), 7.99-8.02 (m, 2H, Ar-H), 9.56 (br, 1H, HCl, +D2O消失), 11.38 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.65 (s, 3H, -NCH 3 ), 2.75-2.56 (m, 2H, -CH 2 CH 2 N-), 2.97-3.13 (m, 4H, -N CH 2 CH 2 O), 3.75-3.80 (m, 2H, -CH 2 CH 2 N-), 3.92-4.03 (m, 4H, -NCH 2 CH 2 O), 4.25-4.31 (m, 2H, Ar- CH 2- ), 5.05 (s, 1H, Ar-CH-), 7.30-7.33 (m, 3H, Ar-H), 7.38-7.44 (m, 2H, Ar-H), 7.49 (s, 1H, Ar -H), 7.59-7.64 (m, 2H, Ar-H), 7.99-8.02 (m, 2H, Ar-H), 9.56 (br, 1H, HCl, + D 2 O disappearance), 11.38 (br, 1H , HCl, + D 2 O disappeared).

実施例 30
N-メチル-3-(ベンゾチオフェン-3-イル)-3-モルホリン-イル-プロピルアミン（VI-30）塩酸塩の調製
N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン（VI-30）の塩酸塩1.36gを得る。収率は75.0%。Mp= 197.5-198.6℃， MS(m/z): 291.1[M+1]+。 Example 30
Preparation of N-methyl-3- (benzothiophen-3-yl) -3-morpholin-yl-propylamine (VI-30) hydrochloride
N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) dissolved in methanol (30 mL) at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 1.36 g of N-methyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine (VI-30) hydrochloride is obtained. Yield 75.0%. Mp = 197.5-198.6 ° C, MS (m / z): 291.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.49-2.51 (m, 2H, -CH 2 CH2N-), 2.96-3.00 (m, 2H, -CH2 CH 2 N-), 3.05-3.25 (m, 4H, -NCH 2 CH2O), 3.47 (s, 3H, N-CH3), 3.85-3.90 (m, 4H, -NCH2 CH 2 O), 4.91-4.94 (d, J=9.6Hz, 1H, Ar-CH-), 7.40-7.43 (m, 2H, Ar-H), 7.49(s, 1H, Ar-H), 8.03-8.05 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.49-2.51 (m, 2H, -CH 2 CH 2 N-), 2.96-3.00 (m, 2H, -CH 2 CH 2 N- ), 3.05-3.25 (m, 4H, -N CH 2 CH 2 O), 3.47 (s, 3H, N-CH 3 ), 3.85-3.90 (m, 4H, -NCH 2 CH 2 O), 4.91-4.94 (d , J = 9.6Hz, 1H, Ar-CH-), 7.40-7.43 (m, 2H, Ar-H), 7.49 (s, 1H, Ar-H), 8.03-8.05 (t, J = 8.4Hz, 2H , Ar-H).

実施例 31
N,N-ジメチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-31）塩酸塩の調製
3-アセチルインドールアセチルインドール(20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.31gを得る。収率は85.5％。MS(m/z): 217.2[M+1]+。 Example 31
Preparation of N, N-dimethyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-31) hydrochloride
3-Acetylindole Acetylindole (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL) and concentrated hydrochloric acid (0.05 mL) is added. Operate to obtain 4.31 g of a white solid. Yield 85.5%. MS (m / z): 217.2 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.37gを得る。収率は93.2%。MS(m/z): 219.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to obtain 2.37 g of a white solid. Yield 93.2%. MS (m / z): 219.1 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-31）の塩酸塩（白色固体）1.24gを得る。収率は43.2%。Mp= 232.5-234.8℃，MS(m/z): 288.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.24 g of hydrochloride (white solid) of N, N-dimethyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-31) . Yield 43.2%. Mp = 232.5-234.8 ° C., MS (m / z): 288.3 [M + 1] + .

1H NMR (CDCl3-d): δ: 2.75-2.81 (m, 2H, -CH 2 CH2N-), 2.85-2.89 (m, 2H, -CH2 CH 2 N-), 2.92-3.01 (m, 2H, -NCH 2 CH2O), 3.28-3.31 (br, 6H, N(CH3)2), 3.82-3.89 (m, 2H, -NCH 2 CH2O), 3.99-4.06 (m, 2H, -NCH2 CH 2 O), 4.12-4.18 (m, 2H, -NCH2 CH 2 O), 5.47-5.50 (d, J=6.4Hz, 1H, Ar-CH-), 7.37-7.58 (m, 2H, Ar-H), 7.81-7.92 (m, 1H, Ar-H), 8.13 (s, 1H, Ar-H), 8.58 (s, 1H, Ar-H), 11.15 (s, 1H, NH)。 1 H NMR (CDCl 3 -d): δ: 2.75-2.81 (m, 2H, -CH 2 CH 2 N-), 2.85-2.89 (m, 2H, -CH 2 CH 2 N- ), 2.92-3.01 ( m, 2H, -N CH 2 CH 2 O), 3.28-3.31 (br, 6H, N (CH 3 ) 2 ), 3.82-3.89 (m, 2H, -N CH 2 CH 2 O), 3.99-4.06 ( m, 2H, -NCH 2 CH 2 O), 4.12-4.18 (m, 2H, -NCH 2 CH 2 O), 5.47-5.50 (d, J = 6.4Hz, 1H, Ar-CH-), 7.37-7.58 (m, 2H, Ar-H), 7.81-7.92 (m, 1H, Ar-H), 8.13 (s, 1H, Ar-H), 8.58 (s, 1H, Ar-H), 11.15 (s, 1H , NH).

実施例 32
N-メチル-N-ベンジル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-32）塩酸塩の調製
3-アセチルインドール(10mmol)、N-メチルベンジルアミン塩酸塩（11mmol）及びパラホルムアルデヒド（13mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.03mL）を加え、一般合成法二の方法Cで操作し、白色固体2.62gを得る。収率は79.8％。MS(m/z): 293.2[M+1]+。 Example 32
Preparation of N-methyl-N-benzyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-32) hydrochloride
3-acetylindole (10 mmol), N-methylbenzylamine hydrochloride (11 mmol) and paraformaldehyde (13 mmol) are dissolved in 95% ethanol (10 mL) and concentrated hydrochloric acid (0.03 mL) is added. To obtain 2.62 g of a white solid. Yield 79.8%. MS (m / z): 293.2 [M + 1] < +>.

前記生成物（7mmol）、水酸化ホウ素ナトリウム（7mmol）をメタノール（30mL）中で、一般合成法三で操作し、白色固体2.18gを得る。収率は94.5%。MS(m/z): 295.1[M+1]+。 The product (7 mmol), sodium borohydride (7 mmol) is operated in methanol (30 mL) according to general synthesis method 3 to obtain 2.18 g of white solid. Yield 94.5%. MS (m / z): 295.1 [M + 1] < +>.

更に、生成物（6mmol）、トリエチルアミン（7.2mmol）、塩化パラトルエンスルホニル（6.6mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（18mmol）、炭酸カリウム（6mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-32）の塩酸塩（白色固体）1.04gを得る。収率は40.0%。Mp= 295.0-297.8℃，MS(m/z): 364.3[M+1]+。 Further, the product (6 mmol), triethylamine (7.2 mmol), p-toluenesulfonyl chloride (6.6 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (18 mmol), potassium carbonate (6 mmol) ), And reacted according to General Synthesis Method 4. Hydrochloric acid salt of N-methyl-N-benzyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-32) (white solid) 1.04 g Get. Yield 40.0%. Mp = 295.0-297.8 ° C., MS (m / z): 364.3 [M + 1] + .

1H NMR (CDCl3-d): δ: 2.45-2.51 (m, 2H, -CH 2 CH2N-), 2.69 (s, 3H, N-CH3), 2.86-2.90 (m, 2H, -CH2 CH 2 N-), 2.92-3.03 (m, 2H, -NCH 2 CH2O), 3.42-3.53 (m, 2H, -NCH 2 CH2O), 3.68-3.75 (m, 2H, -NCH2 CH 2 O), 3.89-3.96 (m, 2H, -NCH2 CH 2 O), 4.25-4.31 (m, 2H, Ar-CH2-), 5.45-5.47 (d, J=6.4Hz, 1H, Ar-CH-), 7.15-7.19 (m, 3H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.37-7.58 (m, 2H, Ar-H), 7.81-7.92 (m, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.56 (s, 1H, Ar-H), 11.13 (s, 1H, NH)。 1 H NMR (CDCl 3 -d): δ: 2.45-2.51 (m, 2H, -CH 2 CH 2 N-), 2.69 (s, 3H, N-CH 3 ), 2.86-2.90 (m, 2H,- CH 2 CH 2 N- ), 2.92-3.03 (m, 2H, -N CH 2 CH 2 O), 3.42-3.53 (m, 2H, -N CH 2 CH 2 O), 3.68-3.75 (m, 2H, -NCH 2 CH 2 O), 3.89-3.96 (m, 2H, -NCH 2 CH 2 O), 4.25-4.31 (m, 2H, Ar-CH 2- ), 5.45-5.47 (d, J = 6.4Hz, 1H, Ar-CH-), 7.15-7.19 (m, 3H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.37-7.58 (m, 2H, Ar-H), 7.81-7.92 (m, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.56 (s, 1H, Ar-H), 11.13 (s, 1H, NH).

実施例 33
N-メチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-33）塩酸塩の調製
N-メチル-N-ベンジル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン（VI-33）の塩酸塩0.81gを得る。収率は78.2%。Mp=178.0-178.6℃， MS(m/z): 274.3[M+1]+。 Example 33
Preparation of N-methyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-33) hydrochloride
N-methyl-N-benzyl-3- (indol-3-yl) -3-morpholinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) was dissolved in methanol (20 mL) at room temperature and normal pressure. Hydrogen is added and reacted for 2 hours, palladium carbon is removed by filtration, and the filtrate is concentrated to obtain a white solid. After recrystallization from absolute ethanol (10 mL), 0.81 g of N-methyl-3- (indol-3-yl) -3-morpholinyl-propylamine (VI-33) hydrochloride is obtained. Yield 78.2%. Mp = 178.0-178.6 ° C, MS (m / z): 274.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.45-2.49 (m, 2H, -CH 2 CH2N-), 2.97-3.02 (m, 2H, -CH2 CH 2 N-), 3.09-3.25 (m, 4H, -NCH 2 CH2O), 3.52 (s, 3H, N-CH3), 3.87-3.93 (m, 4H, -NCH2 CH 2 O), 4.90-4.93 (d, J=9.6Hz, 1H, Ar-CH-), 7.42-7.58 (m, 2H, Ar-H), 7.81-7.90 (m, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 8.59 (s, 1H, Ar-H), 11.13 (s, 1H, NH)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.45-2.49 (m, 2H, -CH 2 CH 2 N-), 2.97-3.02 (m, 2H, -CH 2 CH 2 N- ), 3.09-3.25 (m, 4H, -N CH 2 CH 2 O), 3.52 (s, 3H, N-CH 3 ), 3.87-3.93 (m, 4H, -NCH 2 CH 2 O), 4.90-4.93 (d , J = 9.6Hz, 1H, Ar-CH-), 7.42-7.58 (m, 2H, Ar-H), 7.81-7.90 (m, 1H, Ar-H), 8.10 (s, 1H, Ar-H) , 8.59 (s, 1H, Ar-H), 11.13 (s, 1H, NH).

実施例 34
N,N-ジメチル-3-（5-クロロ-6-メトキシナフタレン-2-イル）-3-モルホリニル-プロピルアミン（VI-34）塩酸塩の調製
1-クロロ-2-メトキシナフタレン（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、3-クロロプロピオン酸クロライド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、3-クロロ-1-（5-クロロ-6-メトキシナフタレン-2-イル）-アセトン 12.7 g（白色固体）を得る。収率は90.0%。MS(m/z): 283.0[M+1]+。 Example 34
Preparation of N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine (VI-34) hydrochloride
Dissolve 1-chloro-2-methoxynaphthalene (0.05 mol) in dichloromethane (30 mL), control the internal temperature to 5 ° C or lower, add AlCl 3 (0.10 mol) in portions, and add 3-chloropropionic acid chloride (0.055 mol). ) And is operated by Method A of General Synthesis Method 1 to obtain 12.7 g (white solid) of 3-chloro-1- (5-chloro-6-methoxynaphthalen-2-yl) -acetone. Yield 90.0%. MS (m / z): 283.0 [M + 1] < +>.

該中間体（0.03mol）、ジメチルアミン水溶液（0.15mol）を無水エタノール（50mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物8.36 gを得る。収率は85.2%。MS(m/z): 292.1[M+1]+。 The intermediate (0.03 mol) and dimethylamine aqueous solution (0.15 mol) are dissolved in absolute ethanol (50 mL) and operated by Method A of General Synthesis Method 2 to obtain 8.36 g of a white solid product. Yield 85.2%. MS (m / z): 292.1 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.94 gを得る。収率は89.5%。MS(m/z): 294.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.94 g of a white solid. Yield 89.5%. MS (m / z): 294.2 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-（5-クロロ-6-メトキシナフタレン-2-イル）-3-モルホリニル-プロピルアミン（VI-34）の塩酸塩（白色固体）1.70 gを得る。収率は48.9%。Mp= 202.5-204.9℃， MS(m/z): 363.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ), And reacted according to General Synthesis Method 4. Hydrochloric acid salt of N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine (VI-34) ( White solid) 1.70 g is obtained. Yield 48.9%. Mp = 202.5-204.9 ° C., MS (m / z): 363.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.42-2.61 (m, 2H, -CH 2 CH2N-), 2.68 (s, 6H, N(CH3)2), 2.75-2.83 (m, 2H, -CH2 CH 2 N-), 2.90-2.95 (m, 4H, -NCH 2 CH2O), 3.72-3.78 (m, 4H, -NCH2 CH 2 O), 4.00 (s, 3H, -OCH3), 4.60-4.62 (d, J=8.8Hz, 1H, Ar-CH-), 7.58-7.60 (d, J=8.8Hz, 1H, Ar-H), 7.73-7.75 (dd, J1=1.2Hz, J2=8.8Hz, 1H, Ar-H), 7.96-7.99 (d, J=8.8Hz, 1H, Ar-H), 8.05-8.08 (t, J=8.8Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.42-2.61 (m, 2H, -CH 2 CH 2 N-), 2.68 (s, 6H, N (CH 3 ) 2 ), 2.75-2.83 (m, 2H, -CH 2 CH 2 N- ), 2.90-2.95 (m, 4H, -N CH 2 CH 2 O), 3.72-3.78 (m, 4H, -NCH 2 CH 2 O), 4.00 (s , 3H, -OCH 3 ), 4.60-4.62 (d, J = 8.8Hz, 1H, Ar-CH-), 7.58-7.60 (d, J = 8.8Hz, 1H, Ar-H), 7.73-7.75 (dd , J 1 = 1.2Hz, J 2 = 8.8Hz, 1H, Ar-H), 7.96-7.99 (d, J = 8.8Hz, 1H, Ar-H), 8.05-8.08 (t, J = 8.8Hz, 2H , Ar-H).

実施例 35
N-メチル-N-ベンジル-3-（5-クロロ-6-メトキシナフタレン-2-イル）-3-モルホリニル-プロピルアミン（VI-35）塩酸塩の調製
3-クロロ-1-（5-クロロ-6-メトキシナフタレン-2-イル）-アセトン（0.05mol）、N-メチルベンジルアミン塩酸塩（0.05mol）、ジイソプロピルエチルアミン(0.15mol) をアセトニトリル（100mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物17.6 gを得る。収率は80.0%。MS(m/z): 368.2[M+1]+。 Example 35
Preparation of N-methyl-N-benzyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine (VI-35) hydrochloride
3-chloro-1- (5-chloro-6-methoxynaphthalen-2-yl) -acetone (0.05 mol), N-methylbenzylamine hydrochloride (0.05 mol), diisopropylethylamine (0.15 mol) in acetonitrile (100 mL) And dissolved in 1 to obtain 17.6 g of a white solid product. Yield 80.0%. MS (m / z): 368.2 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.77 gを得る。収率は85.4%。MS(m/z): 370.2[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 3.77 g of a white solid. Yield 85.4%. MS (m / z): 370.2 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-（5-クロロ-6-メトキシナフタレン-2-イル）-3-モルホリニル-プロピルアミン（VI-35）の塩酸塩（白色固体）1.81gを得る。収率は44.3%。Mp= 248.1-250.3℃， MS(m/z): 439.4 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine (VI-35) hydrochloric acid 1.81 g of salt (white solid) is obtained. Yield 44.3%. Mp = 248.1-250.3 ° C, MS (m / z): 439.4 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.46-2.74 (m, 2H, -CH 2 CH2N-), 2.68 (s, 3H, -NCH3), 2.84-2.94 (m, 2H, -CH2 CH 2 N-), 2.96-3.01 (m, 4H, -NCH 2 CH2O), 3.86 (m, 4H, -NCH2 CH 2 O), 4.01 (s, 3H, -OCH3), 4.26 (s, 2H, Ar-CH2-), 4.59-4.61 (d, J=8.8Hz, 1H, Ar-CH-), 7.26-7.28 (t, J=6.4Hz, 3H, Ar-H), 7.39-7.40 (d, J=6.0Hz, 2H, Ar-H), 7.62-7.64 (d, J=9.2Hz, 1H, Ar-H), 7.76-7.79 (dd, J1=0.8Hz, J2=8.0Hz, 1H, Ar-H), 7.96-7.99 (d, J=8.8Hz, 1H, Ar-H), 8.09-8.11 (t, J=8.8Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.46-2.74 (m, 2H, -CH 2 CH 2 N-), 2.68 (s, 3H, -NCH 3 ), 2.84-2.94 (m, 2H, -CH 2 CH 2 N- ), 2.96-3.01 (m, 4H, -N CH 2 CH 2 O), 3.86 (m, 4H, -NCH 2 CH 2 O), 4.01 (s, 3H, -OCH 3 ), 4.26 (s, 2H, Ar-CH 2- ), 4.59-4.61 (d, J = 8.8Hz, 1H, Ar-CH-), 7.26-7.28 (t, J = 6.4Hz, 3H, Ar- H), 7.39-7.40 (d, J = 6.0Hz, 2H, Ar-H), 7.62-7.64 (d, J = 9.2Hz, 1H, Ar-H), 7.76-7.79 (dd, J 1 = 0.8Hz , J 2 = 8.0Hz, 1H, Ar-H), 7.96-7.99 (d, J = 8.8Hz, 1H, Ar-H), 8.09-8.11 (t, J = 8.8Hz, 2H, Ar-H).

実施例 36
N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-36）塩酸塩の調製
N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-36）の塩酸塩（白色固体）1.5 gを得る。収率は44.9%。Mp= 215.2-216.9℃， MS(m/z):347.2[M+1]+。 Example 36
Preparation of N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-36) hydrochloride
N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) Dissolve in acetonitrile (30 mL), operate according to General Synthesis Method 4. After the reaction, add pyrrolidine (24 mmol) and potassium carbonate (8 mmol), react with General Synthesis Method 4, and react with N, N-dimethyl-3- (5- 1.5 g of hydrochloride (white solid) of chloro-6-methoxynaphthalen-2-yl) -3- (pyrrolidin-1-yl) -propylamine (VI-36) is obtained. Yield 44.9%. Mp = 215.2-216.9 ° C., MS (m / z): 347.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 1.93 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.51-2.62 (m, 2H, NCHCH 2 CH2N), 2.63-2.74 (m, 2H, -NCH 2 CH2CH2 CH 2 N-), 2.68 (s, 6H, -NCH3), 2.91-2.97 (m, 2H, -NCH 2 CH2CH2 CH 2 N-), 3.07 (m, 2H, NCHCH2 CH 2 N), 4.02 (s, 3H, -OCH3), 4.66-4.70 (dd, J1=4.0Hz, J2=9.6Hz, 1H, NCHCH2CH2N), 5.28-5.36 (m, 1H, NCH2 CH=), 7.64-7.66 (d, J=9.2Hz, 1H, Ar-H), 7.98-8.00 (d, J=8.8Hz, 1H, Ar-H), 8.05-8.07 (d, J=8.8Hz, 1H, Ar-H), 8.17-8.19 (d, J=8.8Hz, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 11.50 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d6): δ: 1.93 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.51-2.62 (m, 2H, NCH CH 2 CH 2 N), 2.63-2.74 ( m, 2H, -N CH 2 CH 2 CH 2 CH 2 N-), 2.68 (s, 6H, -NCH 3 ), 2.91-2.97 (m, 2H, -N CH 2 CH 2 CH 2 CH 2 N-) , 3.07 (m, 2H, NCHCH 2 CH 2 N), 4.02 (s, 3H, -OCH 3 ), 4.66-4.70 (dd, J 1 = 4.0Hz, J 2 = 9.6Hz, 1H, N CH CH 2 CH 2 N), 5.28-5.36 (m, 1H, NCH 2 CH =), 7.64-7.66 (d, J = 9.2Hz, 1H, Ar-H), 7.98-8.00 (d, J = 8.8Hz, 1H, Ar -H), 8.05-8.07 (d, J = 8.8Hz, 1H, Ar-H), 8.17-8.19 (d, J = 8.8Hz, 1H, Ar-H), 8.25 (s, 1H, Ar-H) , 11.50 (br, 1H, HCl, + D 2 O disappearance).

実施例 37
N,N-ジメチル-3-(4-メトキシフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-37）塩酸塩の調製
4-メトキシアセトフェノン(20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体3.89gを得る。収率は80.0％。MS(m/z): 208.2[M+1]+。 Example 37
Preparation of N, N-dimethyl-3- (4-methoxyphenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-37) hydrochloride
4-Methoxyacetophenone (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL), concentrated hydrochloric acid (0.05 mL) is added, and operation is performed in Method C of General Synthesis Method 2. To obtain 3.89 g of a white solid. Yield 80.0%. MS (m / z): 208.2 [M + 1] < +>.

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.28gを得る。収率は92.9%。MS(m/z): 210.1[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.28 g of a white solid. Yield 92.9%. MS (m / z): 210.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピロリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(4-メトキシフェニル)-3-(ピロリジン-1-イル)-プロピルアミン（VI-37）の塩酸塩（白色固体）1.07gを得る。収率は40.2%。Mp= 175.2-178.4℃，MS(m/z): 263.4[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, pyrrolidine (24 mmol), potassium carbonate (8 mmol) ), And reacted according to General Synthesis Method 4. Hydrochloric acid salt of N, N-dimethyl-3- (4-methoxyphenyl) -3- (pyrrolidin-1-yl) -propylamine (VI-37) (white solid ) Get 1.07g. Yield 40.2%. Mp = 175.2-178.4 ° C, MS (m / z): 263.4 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.82-1.86 (m, 4H, -NCH2 CH 2 CH 2 CH2N-), 2.53-2.58 (m, 2H, -CH 2 CH2N-), 2.68 (s, 6H, N(CH3)2), 2.90-2.97(m, 2H, -CH2 CH 2 N-), 3.13 (m, 4H, -NCH 2 CH2CH2 CH 2 N-), 4.69 (s, 3H, -OCH3), 4.94-4.97 (d, J=9.6Hz, 1H, Ar-CH-), 6.62-6.65 (d, J=8.8Hz, 2H, Ar-H), 7.26-7.29 (t, J=8.8Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.82-1.86 (m, 4H, -NCH 2 CH 2 CH 2 CH 2 N-), 2.53-2.58 (m, 2H, -CH 2 CH 2 N-), 2.68 (s, 6H, N (CH 3 ) 2 ), 2.90-2.97 (m, 2H, -CH 2 CH 2 N- ), 3.13 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 N-), 4.69 (s, 3H, -OCH 3 ), 4.94-4.97 (d, J = 9.6Hz, 1H, Ar-CH-), 6.62-6.65 (d, J = 8.8Hz, 2H, Ar- H), 7.26-7.29 (t, J = 8.8Hz, 2H, Ar-H).

実施例 38
N,N-ジメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン（VI-38）塩酸塩の調製
N,N-ジメチル-3-(4-メトキシフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン（VI-38）の塩酸塩（白色固体）1.12 gを得る。収率は40.0%。Mp= 184.0-187.2℃， MS(m/z): 279.4[M+1]+。 Example 38
Preparation of N, N-dimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine (VI-38) hydrochloride
N, N-dimethyl-3- (4-methoxyphenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) are dissolved in acetonitrile (30 mL). Operate in Synthesis Method 4 and, after the reaction, add morpholine (24 mmol) and potassium carbonate (8 mmol), react in General Synthesis Method 4, and react with N, N-dimethyl-3- (4-methoxyphenyl) -3-morpholinyl- 1.12 g of hydrochloride (white solid) of propylamine (VI-38) is obtained. Yield 40.0%. Mp = 184.0-187.2 ° C, MS (m / z): 279.4 [M + 1] + .

1H NMR (CDCl3+DMSO-d6): δ: 2.14-2.41 (m, 2H, -CH 2 CH2N-), 2.36-2.41 (ds, 6H, N(CH3)2), 2.47-2.74 (m, 4H, -NCH 2 CH2O ), 3.29-3.87 (m, 4H, -NCH2 CH 2 O), 3.41 (s, 3H, -OCH3), 3.52-3.53 (d, J=4.8Hz, 2H, -CH2 CH 2 N-), 4.29-4.31 (d, J=8.4Hz, 1H, Ar-CH-), 6.55-6.58 (d, J=8.4Hz, 2H, Ar-H), 7.25-7.28 (t, J=8.4Hz, 2H, Ar-H), 11.25 (br, 1H, HCl, +D2O消失), 12.00 (br, 1H, HCl, +D2O消失)。 1 H NMR (CDCl 3 + DMSO-d 6 ): δ: 2.14-2.41 (m, 2H, -CH 2 CH2N-), 2.36-2.41 (ds, 6H, N (CH 3 ) 2 ), 2.47-2.74 ( m, 4H, -N CH 2 CH 2 O), 3.29-3.87 (m, 4H, -NCH 2 CH 2 O), 3.41 (s, 3H, -OCH 3 ), 3.52-3.53 (d, J = 4.8Hz , 2H, -CH 2 CH 2 N-), 4.29-4.31 (d, J = 8.4Hz, 1H, Ar-CH-), 6.55-6.58 (d, J = 8.4Hz, 2H, Ar-H), 7.25 -7.28 (t, J = 8.4Hz, 2H, Ar-H), 11.25 (br, 1H, HCl, + D 2 O disappeared), 12.00 (br, 1H, HCl, + D 2 O disappeared).

実施例 39
N,N,2-トリメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン（VI-39）塩酸塩の調製
4-メトキシフェニルアセトン(20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体3.95gを得る。収率は76.8％。MS(m/z): 222.1[M+1]+。 Example 39
Preparation of N, N, 2-trimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine (VI-39) hydrochloride
4-Methoxyphenylacetone (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL), concentrated hydrochloric acid (0.05 mL) is added, and operation is performed in Method C of General Synthesis Method 2. To obtain 3.95 g of a white solid. Yield 76.8%. MS (m / z): 222.1 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.35gを得る。収率は90.7%。MS(m/z): 224.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.35 g of a white solid. Yield 90.7%. MS (m / z): 224.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N,2-トリメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン（VI-39）の塩酸塩（白色固体）1.44gを得る。収率は49.5%。Mp= 235.6-238.9℃，MS(m/z): 293.4[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.44 g of hydrochloride (white solid) of N, N, 2-trimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine (VI-39) obtain. Yield 49.5%. Mp = 235.6-238.9 ° C., MS (m / z): 293.4 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 0.98 (d, J=7.6Hz, 3H, CHCH 3 ), 2.20-2.25 (m, 2H, -ArCHCHCH 2 N-), 2.65 (s, 6H, N(CH3)2), 2.70-2.75 (m, 1H, -ArCHCHCH2N-), 2.97-3.05 (m, 4H, -NCH 2 CH2O ), 3.24-3.29 (m, 4H, -NCH2 CH 2 O), 4.69 (s, 3H, -OCH3), 4.21-4.23 (d, J=8.8Hz, 1H, Ar-CH-), 6.56-6.58 (d, J=8.4Hz, 2H, Ar-H), 7.26-7.29 (t, J=8.4Hz, 2H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 0.98 (d, J = 7.6Hz, 3H, CH CH 3 ), 2.20-2.25 (m, 2H, -ArCHCH CH 2 N-), 2.65 ( s, 6H, N (CH 3 ) 2 ), 2.70-2.75 (m, 1H, -ArCH CH CH 2 N-), 2.97-3.05 (m, 4H, -N CH 2 CH 2 O), 3.24-3.29 ( m, 4H, -NCH 2 CH 2 O), 4.69 (s, 3H, -OCH 3 ), 4.21-4.23 (d, J = 8.8Hz, 1H, Ar-CH-), 6.56-6.58 (d, J = 8.4Hz, 2H, Ar-H), 7.26-7.29 (t, J = 8.4Hz, 2H, Ar-H).

実施例 40
N,N-ジメチル-2-((3,4-ジクロロフェニル)(モルホリン)メチル)-1-ヘプチルアミン（VI-40）塩酸塩の調製
1,2-ジクロロベンゼン（0.07mol）にAlCl3(0.07mol)を加え、70℃まで加熱し、撹拌下で、ヘプタノイルクロライド（0.077mol）を滴下し、一般合成法一の方法Bで操作し、1-（3，4-ジクロロフェニル）-ヘプタノン 16.0 g（白色固体）を得る。収率は88.6%（1,2-ジクロロベンゼンで計算）。MS(m/z): 259.1[M+1]+。 Example 40
Preparation of N, N-dimethyl-2-((3,4-dichlorophenyl) (morpholine) methyl) -1-heptylamine (VI-40) hydrochloride
Add AlCl 3 (0.07 mol) to 1,2-dichlorobenzene (0.07 mol), heat to 70 ° C, add dropwise heptanoyl chloride (0.077 mol) with stirring, and operate in Method B of General Synthesis Method 1. 16.0 g (white solid) of 1- (3,4-dichlorophenyl) -heptanone is obtained. Yield 88.6% (calculated with 1,2-dichlorobenzene). MS (m / z): 259.1 [M + 1] < +>.

該中間体（50mol）、ジメチルアミン塩酸塩（55mmol）及びパラホルムアルデヒド（65mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.2mL）を加え、一般合成法二の方法Cで操作し、白色固体14.2gを得る。収率は80.9％。MS(m/z): 316.1[M+1]+。 Dissolve the intermediate (50 mol), dimethylamine hydrochloride (55 mmol) and paraformaldehyde (65 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.2 mL), and operate in General Synthesis Method 2, Method C; 14.2 g of a white solid is obtained. Yield 80.9%. MS (m / z): 316.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.8 gを得る。収率は79.3%。MS(m/z): 318.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 2.8 g of a white solid. Yield 79.3%. MS (m / z): 318.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-2-((3,4-ジクロロフェニル)(モルホリン)メチル)-1-ヘプチルアミン（VI-1）の塩酸塩（白色固体）1.8 gを得る。収率は49.1%。MS(m/z): 387.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ), And the reaction is carried out according to General Synthesis Method 4. Hydrochloric acid salt of N, N-dimethyl-2-((3,4-dichlorophenyl) (morpholine) methyl) -1-heptylamine (VI-1) (white solid) Obtain 1.8 g. Yield 49.1%. MS (m / z): 387.2 [M + 1] +.

1H NMR (DMSO-d6): δ: 0.92 (t, J=7.2Hz, 3H, CH2 CH 3 ), 1.35 ( m, 3H, CH(CH 2 )4CH3), 2.18-2.23 (m, 2H, -ArCHCHCH 2 N-), 2.66 (s, 6H, N(CH3)2), 2.70-2.73 (m, 1H, -ArCHCHCH2N-), 2.99-3.03 (m, 4H, -NCH 2 CH2O ), 3.21-3.26 (m, 4H, -NCH2 CH 2 O), 4.65 (s, 1H, Ar-CH-), 7.75-7.77 (dd, J1=8.4Hz, J2=3.2Hz, 2H, Ar-H), 8.10 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ): δ: 0.92 (t, J = 7.2Hz, 3H, CH 2 CH 3 ), 1.35 (m, 3H, CH ( CH 2 ) 4 CH 3 ), 2.18-2.23 (m , 2H, -ArCHCH CH 2 N-), 2.66 (s, 6H, N (CH 3 ) 2 ), 2.70-2.73 (m, 1H, -ArCH CH CH 2 N-), 2.99-3.03 (m, 4H, -N CH 2 CH 2 O), 3.21-3.26 (m, 4H, -NCH 2 CH 2 O), 4.65 (s, 1H, Ar-CH-), 7.75-7.77 (dd, J 1 = 8.4Hz, J 2 = 3.2Hz, 2H, Ar-H), 8.10 (s, 1H, Ar-H).

実施例 41
N,N-ジメチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-41）塩酸塩の調製
2,3-ジヒドロベンゾフラン（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、3-クロロプロピオン酸クロライド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、3-クロロ-1-(2,3-ジヒドロベンゾフラン-5-イル)-アセトン 8.4g（白色固体）を得る。収率は80.2%。MS(m/z): 211.0[M+1]+。 Example 41
Preparation of N, N-dimethyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-41) hydrochloride
Dissolve 2,3-dihydrobenzofuran (0.05 mol) in dichloromethane (30 mL), control the internal temperature to 5 ° C or lower, add AlCl 3 (0.10 mol) in portions, and add 3-chloropropionic acid chloride (0.055 mol). Add dropwise and operate in Method A of General Synthesis Method 1 to obtain 8.4 g of 3-chloro-1- (2,3-dihydrobenzofuran-5-yl) -acetone (white solid). Yield 80.2%. MS (m / z): 211.0 [M + 1] < +>.

該中間体（0.03mol）、ジメチルアミン水溶液（0.15mol）を無水エタノール（50mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物5.78gを得る。収率は75.6%。MS(m/z): 220.2[M+1]+。 The intermediate (0.03 mol) and dimethylamine aqueous solution (0.15 mol) are dissolved in absolute ethanol (50 mL) and operated by Method A of General Synthesis Method 2 to obtain 5.78 g of a white solid product. Yield 75.6%. MS (m / z): 220.2 [M + 1] < +>.

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.38gを得る。収率は92.3%。MS(m/z): 222.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.38 g of a white solid. Yield 92.3%. MS (m / z): 222.2 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）に加え、一般合成法四で反応させ、N,N-ジメチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-41）の塩酸塩（白色固体）1.17gを得る。収率は40.5%。Mp= 234.5-236.9℃， MS(m/z): 291.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And N, N-dimethyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-41) hydrochloride (white solid) ) 1.17g is obtained. Yield 40.5%. Mp = 234.5-236.9 ° C., MS (m / z): 291.3 [M + 1] + .

1H NMR (DMSO-d6): δ: 1.99-2.22 (m, 2H, -CH 2 CH2N-), 2.36-2.48 (m, 2H, -CH2 CH 2 N-), 2.69 (s, 6H, N(CH3)2), 2.75-2.89 (m, 4H, -NCH 2 CH2O), 3.01-3.04 (d, J=8.8Hz, 2H, ArCH 2 CH2O), 3.63-3.68 (m, 4H, -NCH2 CH 2 O), 3.76-3.78 (t, J=7.2Hz, 1H, Ar-CH-), 4.25-4.28 (d, J=8.8Hz, 2H, ArCH2 CH 2 O), 7.21-7.23 (dd, J1=1.6Hz, J2=8.0Hz, 1H, Ar-H), 7.35-7.38 (dd, J1=1.6Hz, J2=8.0Hz, 1H, Ar-H), 7.62-7.64 (d, J=8.4Hz, 1H, Ar-H), 10.51 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 1.99-2.22 (m, 2H, -CH 2 CH 2 N-), 2.36-2.48 (m, 2H, -CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.75-2.89 (m, 4H, -N CH 2 CH 2 O), 3.01-3.04 (d, J = 8.8Hz, 2H, Ar CH 2 CH 2 O), 3.63- 3.68 (m, 4H, -NCH 2 CH 2 O), 3.76-3.78 (t, J = 7.2Hz, 1H, Ar-CH-), 4.25-4.28 (d, J = 8.8Hz, 2H, ArCH 2 CH 2 O), 7.21-7.23 (dd, J 1 = 1.6Hz, J 2 = 8.0Hz, 1H, Ar-H), 7.35-7.38 (dd, J 1 = 1.6Hz, J 2 = 8.0Hz, 1H, Ar- H), 7.62-7.64 (d, J = 8.4 Hz, 1H, Ar-H), 10.51 (br, 1H, HCl, + D 2 O disappearance).

実施例 42
N-メチル-N-ベンジル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-42）塩酸塩の調製
3-クロロ-1-(2,3-ジヒドロベンゾフラン-5-イル)-アセトン（0.02mol）、N-メチルベンジルアミン塩酸塩（0.02mol）、ジイソプロピルエチルアミン(0.06mol) をアセトニトリル（60mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物5.20gを得る。収率は78.5%。MS(m/z): 296.2[M+1]+。 Example 42
Preparation of N-methyl-N-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-42) hydrochloride
3-Chloro-1- (2,3-dihydrobenzofuran-5-yl) -acetone (0.02 mol), N-methylbenzylamine hydrochloride (0.02 mol) and diisopropylethylamine (0.06 mol) are dissolved in acetonitrile (60 mL). Operate in Method B of General Synthesis Method 2 to obtain 5.20 g of a white solid product. Yield 78.5%. MS (m / z): 296.2 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.0gを得る。収率は90.2%。MS(m/z): 298.1[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 3.0 g of a white solid. Yield 90.2%. MS (m / z): 298.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-42）の塩酸塩（白色固体）1.4gを得る。収率は40.0%。Mp= 265.0-268.5℃， MS(m/z): 367.4[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ), And the reaction is carried out according to General Synthesis Method 4. The hydrochloride salt of N-methyl-N-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-42) ( 1.4 g of a white solid is obtained. Yield 40.0%. Mp = 265.0-268.5 ° C, MS (m / z): 367.4 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.43-2.55 (m, 2H, -CH 2 CH2N-), 2.49-2.58 (m, 2H, -NCH 2 CH2O), 2.69 (s, 3H, -NCH3), 2.83-2.91 (m, 2H, -CH2 CH 2 N-), 3.01-3.08 (m, 2H, -NCH 2 CH2O), 3.12-3.15 (d, J=8.8Hz, 2H, ArCH 2 CH2O), 3.62-3.69 (m, 4H, -NCH2 CH 2 O), 4.21 (s, 2H, Ar-CH2-), 4.29-4.31 (d, J=6.4Hz, 1H, Ar-CH-), 4.27-4.30 (d, J=8.8Hz, 2H, ArCH2 CH 2 O), 7.30-7.36 (m, 6H, Ar-H), 7.62-7.64 (d, J=8.4Hz, 1H, Ar-H), 7.72 (d, J=2.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.43-2.55 (m, 2H, -CH 2 CH 2 N-), 2.49-2.58 (m, 2H, -N CH 2 CH 2 O), 2.69 (s, 3H, -NCH 3 ), 2.83-2.91 (m, 2H, -CH 2 CH 2 N- ), 3.01-3.08 (m, 2H, -N CH 2 CH 2 O), 3.12-3.15 (d , J = 8.8Hz, 2H, Ar CH 2 CH 2 O), 3.62-3.69 (m, 4H, -NCH 2 CH 2 O), 4.21 (s, 2H, Ar-CH 2- ), 4.29-4.31 (d , J = 6.4Hz, 1H, Ar-CH-), 4.27-4.30 (d, J = 8.8Hz, 2H, ArCH 2 CH 2 O), 7.30-7.36 (m, 6H, Ar-H), 7.62-7.64 (d, J = 8.4Hz, 1H, Ar-H), 7.72 (d, J = 2.0Hz, 1H, Ar-H).

実施例 43
N-メチル-3-(2,3- ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-43）塩酸塩の調製
N-メチル-N-ベンジル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン（VI-43）の塩酸塩0.89gを得る。収率は85.0%。Mp=172.5-175.9℃， MS(m/z): 277.3[M+1]+。 Example 43
Preparation of N-methyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-43) hydrochloride
N-methyl-N-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) was dissolved in methanol (20 mL). Hydrogen is added at room temperature and normal pressure, and the mixture is reacted for 2 hours. Palladium carbon is removed by filtration, and the filtrate is concentrated to obtain a white solid. After recrystallization from absolute ethanol (10 mL), 0.89 g of N-methyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine (VI-43) hydrochloride is obtained. Yield 85.0%. Mp = 172.5-175.9 ° C, MS (m / z): 277.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.35-2.42 (m, 2H, -CH 2 CH2N-), 2.71-2.79 (m, 2H, -CH2 CH 2 N-), 3.02-3.07 (m, 4H, -NCH 2 CH2O), 3.10-3.13 (d, J=8.8Hz, 2H, ArCH 2 CH2O), 3.25 (s, 3H, -NCH3), 3.61-3.67 (m, 4H, -NCH2 CH 2 O), 4.27-4.30 (d, J=8.0Hz, 1H, Ar-CH-), 4.37-4.39 (d, J=8.8Hz, 2H, ArCH2 CH 2 O), 7.28-7.31 (d, J=8.4Hz, 1H, Ar-H), 7.60-7.63 (d, J=8.4Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.35-2.42 (m, 2H, -CH 2 CH 2 N-), 2.71-2.79 (m, 2H, -CH 2 CH 2 N- ), 3.02-3.07 (m, 4H, -N CH 2 CH 2 O), 3.10-3.13 (d, J = 8.8Hz, 2H, Ar CH 2 CH 2 O), 3.25 (s, 3H, -NCH 3 ), 3.61 -3.67 (m, 4H, -NCH 2 CH 2 O), 4.27-4.30 (d, J = 8.0Hz, 1H, Ar-CH-), 4.37-4.39 (d, J = 8.8Hz, 2H, ArCH 2 CH 2 O), 7.28-7.31 (d, J = 8.4Hz, 1H, Ar-H), 7.60-7.63 (d, J = 8.4Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H) .

実施例 44
N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-モルホリニル-ブチルアミン（VI-44）塩酸塩の調製
1,2-ジクロロベンゼン（0.1mol）にAlCl3(0.1mol)を加え、70℃まで加熱し、4-クロロブチリルクロリド（0.11mol）を滴下し、一般合成法一の方法Bで操作し、4-クロロ-1-（3，4-ジクロロフェニル）-ブタノン 21.0 g（白色固体）を得る。収率は84.0%（1,2-ジクロロベンゼンで計算）。MS(m/z): 251.1[M+1]+。 Example 44
Preparation of N, N-dimethyl-4- (3,4-dichlorophenyl) -4-morpholinyl-butylamine (VI-44) hydrochloride
Add AlCl 3 (0.1 mol) to 1,2-dichlorobenzene (0.1 mol), heat to 70 ° C, add 4-chlorobutyryl chloride (0.11 mol) dropwise, and operate in Method B of General Synthesis Method 1. 4-chloro-1- (3,4-dichlorophenyl) -butanone 21.0 g (white solid) is obtained. Yield 84.0% (calculated with 1,2-dichlorobenzene). MS (m / z): 251.1 [M + 1] < +>.

該中間体（0.05mol）、ジメチルアミン水溶液（0.25mol）を無水エタノール（100mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物11.5 gを得る。収率は81.9%。MS(m/z): 260.1[M+1]+。 Dissolve the intermediate (0.05 mol) and dimethylamine aqueous solution (0.25 mol) in absolute ethanol (100 mL), and operate by General Synthesis Method 2 Method A to obtain 11.5 g of a white solid product. Yield 81.9%. MS (m / z): 260.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.7 gを得る。収率は90.9%。MS(m/z): 262.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.7 g of a white solid. Yield 90.9%. MS (m / z): 262.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-モルホリニル-ブチルアミン（VI-44）の塩酸塩（白色固体）1.6 gを得る。収率は49.8%。Mp= 232.3-233.7℃， MS(m/z): 331.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.6 g of N, N-dimethyl-4- (3,4-dichlorophenyl) -4-morpholinyl-butylamine (VI-44) hydrochloride (white solid). Yield 49.8%. Mp = 232.3-233.7 ° C., MS (m / z): 331.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ:1.89-1.93 (m, 2H, -CHCH2 CH 2 CH2N-), 1.97-2.01 (m, 2H, -CHCH 2 CH2CH2N-), 2.69 (s, 6H, N(CH3)2), 2.75-2.79 (m, 2H, CHCH2CH2 CH 2 N-), 2.94-3.00 (m, 4H, -NCH 2 CH2O), 3.75 (m, 4H, -NCH2 CH 2 O), 4.66-4.68 (d, J=8.0Hz, 1H, Ar-CH-), 7.26-7.28 (dd, J1=2.0Hz, J2=8.4Hz, 1H, Ar-H), 7.48 (d, J=2.0Hz, 1H, Ar-H), 7.61-7.63 (d, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.89-1.93 (m, 2H, -CHCH 2 CH 2 CH 2 N-), 1.97-2.01 (m, 2H, -CH CH 2 CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.75-2.79 (m, 2H, CHCH 2 CH 2 CH 2 N-), 2.94-3.00 (m, 4H, -N CH 2 CH 2 O), 3.75 (m, 4H, -NCH 2 CH 2 O), 4.66-4.68 (d, J = 8.0Hz, 1H, Ar-CH-), 7.26-7.28 (dd, J 1 = 2.0Hz, J 2 = 8.4Hz, 1H, Ar-H), 7.48 (d, J = 2.0Hz, 1H, Ar-H), 7.61-7.63 (d, J = 8.0Hz, 1H, Ar-H).

実施例 45
N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-(ピペラジン-1-イル)-ブチルアミン（VI-45）塩酸塩の調製
N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-ヒドロキシ-ブチルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペラジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-(ピペラジン-1-イル)-ブチルアミン（VI-45）の塩酸塩（白色固体）1.51gを得る。収率は43.2%。Mp=245.6-248.2℃， MS(m/z): 330.3[M+1]+。 Example 45
Preparation of N, N-dimethyl-4- (3,4-dichlorophenyl) -4- (piperazin-1-yl) -butylamine (VI-45) hydrochloride
N, N-dimethyl-4- (3,4-dichlorophenyl) -4-hydroxy-butylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) are dissolved in acetonitrile (30 mL). Operate in Synthesis Method 4, and after the reaction, piperazine (24 mmol) and potassium carbonate (8 mmol) are added and reacted in General Synthesis Method 4. N, N-dimethyl-4- (3,4-dichlorophenyl) -4- ( 1.51 g of hydrochloride (white solid) of piperazin-1-yl) -butylamine (VI-45) is obtained. Yield 43.2%. Mp = 245.6-248.2 ° C, MS (m / z): 330.3 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ:1.90-1.93 (m, 2H, -CHCH2 CH 2 CH2N-), 1.95-1.98 (m, 2H, -CHCH 2 CH2CH2N-), 2.69 (s, 6H, N(CH3)2), 2.75-2.78 (m, 2H, CHCH2CH2 CH 2 N-), 2.92-2.96 (m, 4H, -NCH 2 CH2NH), 2.99-3.03 (m, 4H, -NCH2 CH 2 NH), 4.65-4.67 (d, J=8.0Hz, 1H, Ar-CH-), 7.25-7.27 (dd, J1=2.0Hz, J2=8.4Hz, 1H, Ar-H), 7.49 (d, J=2.0Hz, 1H, Ar-H), 7.58-7.60 (d, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.90-1.93 (m, 2H, -CHCH 2 CH 2 CH 2 N-), 1.95-1.98 (m, 2H, -CH CH 2 CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.75-2.78 (m, 2H, CHCH 2 CH 2 CH 2 N-), 2.92-2.96 (m, 4H, -N CH 2 CH 2 NH), 2.99-3.03 (m, 4H, -NCH 2 CH 2 NH), 4.65-4.67 (d, J = 8.0Hz, 1H, Ar-CH-), 7.25-7.27 (dd, J 1 = 2.0Hz , J 2 = 8.4Hz, 1H, Ar-H), 7.49 (d, J = 2.0Hz, 1H, Ar-H), 7.58-7.60 (d, J = 8.0Hz, 1H, Ar-H).

実施例 46
N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-モルホリニル-ブチルアミン（VI-46）塩酸塩の調製
ベンゾチオフェン（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、4-クロロブチリルクロリド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、4-クロロ-1-(ベンゾチオフェン-3-イル)-ブタノン 9.5 g（白色固体）を得る。収率は79.8%。MS(m/z): 239.0[M+1]+。 Example 46
Preparation of N, N-dimethyl-4- (benzothiophen-3-yl) -4-morpholinyl-butylamine (VI-46) hydrochloride Dissolve benzothiophene (0.05 mol) in dichloromethane (30 mL), and the internal temperature is below 5 ° C. In this manner, AlCl 3 (0.10 mol) was added in portions, 4-chlorobutyryl chloride (0.055 mol) was added dropwise, and the procedure was performed according to Method A of General Synthesis Method 4-chloro-1- (benzothiophene). 9.5 g (white solid) of 3-yl) -butanone are obtained. Yield 79.8%. MS (m / z): 239.0 [M + 1] + .

該中間体（0.03mol）、ジメチルアミン水溶液（0.15mol）を無水エタノール（50mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物6.7gを得る。収率は78.9%。MS(m/z): 248.1[M+1]+。 The intermediate (0.03 mol) and dimethylamine aqueous solution (0.15 mol) are dissolved in absolute ethanol (50 mL) and operated by Method A of General Synthesis Method 2 to obtain 6.7 g of a white solid product. Yield 78.9%. MS (m / z): 248.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.43 gを得る。収率は85.3%。MS(m/z): 250.1[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in general synthetic method 3 in methanol (50 mL) to give 2.43 g of a white solid. Yield 85.3%. MS (m / z): 250.1 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-モルホリニル-ブチルアミン（VI-46）の塩酸塩（白色固体）1.54 gを得る。収率は49.4%。Mp= 242.7-244.2℃， MS(m/z): 319.1[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.54 g of hydrochloride (white solid) of N, N-dimethyl-4- (benzothiophen-3-yl) -4-morpholinyl-butylamine (VI-46) . Yield 49.4%. Mp = 242.7-244.2 ° C, MS (m / z): 319.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 1.87-1.90 (m, 2H, -CHCH2 CH 2 CH2N-), 1.95-1.98 (m, 2H, -CHCH 2 CH2CH2N-), 2.67 (s, 6H, N(CH3)2), 2.73-2.76 (m, 2H, CHCH2CH2 CH 2 N-), 2.94-2.98 (m, 4H, -NCH 2 CH2O), 3.73 (m, 4H, -NCH2 CH 2 O), 5.48-5.50 (d, J=6.4Hz, 1H, Ar-CH-), 7.44-7.63 (m, 2H, Ar-H), 7.87-7.99 (m, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 8.62 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.87-1.90 (m, 2H, -CHCH 2 CH 2 CH 2 N-), 1.95-1.98 (m, 2H, -CH CH 2 CH 2 CH 2 N-), 2.67 (s, 6H, N (CH 3 ) 2 ), 2.73-2.76 (m, 2H, CHCH 2 CH 2 CH 2 N-), 2.94-2.98 (m, 4H, -N CH 2 CH 2 O), 3.73 (m, 4H, -NCH 2 CH 2 O), 5.48-5.50 (d, J = 6.4Hz, 1H, Ar-CH-), 7.44-7.63 (m, 2H, Ar-H), 7.87-7.99 (m, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 8.62 (s, 1H, Ar-H).

実施例 47
N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-(ピペラジン-1-イル)-ブチルアミン（VI-47）塩酸塩の調製
N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-ヒドロキシ-ブチルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペラジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-(ピペラジン-1-イル)-ブチルアミン（VI-47）の塩酸塩（白色固体）1.68gを得る。収率は49.4%。Mp=249.6-252.2℃， MS(m/z): 318.1[M+1]+。 Example 47
Preparation of N, N-dimethyl-4- (benzothiophen-3-yl) -4- (piperazin-1-yl) -butylamine (VI-47) hydrochloride
N, N-dimethyl-4- (benzothiophen-3-yl) -4-hydroxy-butylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operate according to General Synthesis Method 4, and after the reaction, add piperazine (24 mmol) and potassium carbonate (8 mmol), and react with General Synthesis Method 4. N, N-dimethyl-4- (benzothiophen-3-yl) -4 1.68 g of hydrochloride salt (white solid) of-(piperazin-1-yl) -butylamine (VI-47) are obtained. Yield 49.4%. Mp = 249.6-252.2 ° C, MS (m / z): 318.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ:1.90-1.92 (m, 2H, -CHCH2 CH 2 CH2N-), 1.96-1.99 (m, 2H, -CHCH 2 CH2CH2N-), 2.65 (s, 6H, N(CH3)2), 2.72-2.75 (m, 2H, CHCH2CH2 CH 2 N-), 2.92-2.95 (m, 4H, -NCH 2 CH2NH), 2.97-3.01 (m, 4H, -NCH2 CH 2 NH), 5.45-5.47 (d, J=6.4Hz, 1H, Ar-CH-), 7.44-7.52 (m, 2H, Ar-H), 7.87-7.95 (m, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 8.59 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.90-1.92 (m, 2H, -CHCH 2 CH 2 CH 2 N-), 1.96-1.99 (m, 2H, -CH CH 2 CH 2 CH 2 N-), 2.65 (s, 6H, N (CH 3 ) 2 ), 2.72-2.75 (m, 2H, CHCH 2 CH 2 CH 2 N-), 2.92-2.95 (m, 4H, -N CH 2 CH 2 NH), 2.97-3.01 (m, 4H, -NCH 2 CH 2 NH), 5.45-5.47 (d, J = 6.4Hz, 1H, Ar-CH-), 7.44-7.52 (m, 2H, Ar-H ), 7.87-7.95 (m, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 8.59 (s, 1H, Ar-H).

実施例 48
N,N-ジメチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-48）塩酸塩の調製
2,4-ジフルオロベンゾフェノン (20mmol)、ジメチルアミン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.23gを得る。収率は85.0％。MS(m/z): 214.0[M+1]+。 Example 48
Preparation of N, N-dimethyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-48) hydrochloride
Dissolve 2,4-difluorobenzophenone (20 mmol), dimethylamine hydrochloride (22 mmol) and paraformaldehyde (26 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.05 mL), and use General Synthesis Method 2 Method C. Operate to obtain 4.23 g of white solid. Yield 85.0%. MS (m / z): 214.0 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.14gを得る。収率は85.2%。MS(m/z): 216.0[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.14 g of a white solid. Yield 85.2%. MS (m / z): 216.0 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-48）の塩酸塩（白色固体）1.57 gを得る。収率は55.0%。Mp= 245.8-248.0℃， MS(m/z): 285.2 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.57 g of hydrochloride (white solid) of N, N-dimethyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-48) obtain. Yield 55.0%. Mp = 245.8-248.0 ° C, MS (m / z): 285.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.61-2.66 (m, 2H, -CH 2 CH2N-), 2.39-2.42 (m, 1H, -CH 2 CH2N-), 2.71 (s, 6H, N(CH3)2), 2.78-2.84 (m, 2H, -CH2 CH 2 N-), 2.93-3.03 (m, 4H, -NCH 2 CH2O), 3.90 (m, 4H, -NCH2 CH 2 O), 4.67-4.69 (d, J=7.2Hz, 1H, Ar-CH-), 7.25-7.30 (m, 1H, Ar-H), 7.37-7.43 (m, 1H, Ar-H), 8.02-8.03 (d, J=6.4Hz, 1H, Ar-H), 10.95 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.61-2.66 (m, 2H, -CH 2 CH 2 N-), 2.39-2.42 (m, 1H, -CH 2 CH 2 N-), 2.71 (s, 6H, N (CH 3 ) 2 ), 2.78-2.84 (m, 2H, -CH 2 CH 2 N-), 2.93-3.03 (m, 4H, -N CH 2 CH 2 O), 3.90 (m, 4H, -NCH 2 CH 2 O), 4.67-4.69 (d, J = 7.2Hz, 1H, Ar-CH-), 7.25-7.30 (m, 1H, Ar-H), 7.37-7.43 (m, 1H, Ar- H), 8.02-8.03 (d, J = 6.4 Hz, 1H, Ar—H), 10.95 (br, 1H, HCl, + D 2 O disappearance).

実施例 49
N-メチル-N-ベンジル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-49）塩酸塩の調製
2,4-ジフルオロベンゾフェノン(20mmol)、N-メチルアニリン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.55gを得る。収率は70.0％。MS(m/z): 290.1[M+1]+。 Example 49
Preparation of N-methyl-N-benzyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-49) hydrochloride
Method of General Synthesis Method 2 Dissolve 2,4-difluorobenzophenone (20 mmol), N-methylaniline hydrochloride (22 mmol) and paraformaldehyde (26 mmol) in 95% ethanol (10 mL), add concentrated hydrochloric acid (0.05 mL). Operate with C to give 4.55 g of white solid. Yield is 70.0%. MS (m / z): 290.1 [M + 1] < +>.

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.95gを得る。収率は90.2%。MS(m/z): 292.0[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.95 g of a white solid. Yield 90.2%. MS (m / z): 292.0 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-49）の塩酸塩（白色固体）2.07 gを得る。収率は60.0%。Mp= 228.5-231.2℃， MS(m/z): 361.2 [M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-49) hydrochloride (white solid) 2.07 get g. Yield 60.0%. Mp = 228.5-231.2 ° C, MS (m / z): 361.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.40-2.79 (m, 2H, -CH 2 CH2N-), 2.67 (s, 3H, -NCH3), 2.86-3.05 (m, 2H, -CH2 CH 2 N-), 3.47-3.67 (m, 4H, -NCH 2 CH2O), 3.74-3.75 (m, 4H, -NCH2 CH 2 O), 4.27 (s, 2H, Ar-CH2-), 4.45 (s, 1H, Ar-CH-), 7.12-7.17 (m, 1H, Ar-H), 7.23-7.28 (m, 1H, Ar-H), 7.37-7.41 (m, 3H, Ar-H), 7.42-7.50 (m, 2H, Ar-H), 7.65-7.71 (q, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.40-2.79 (m, 2H, -CH 2 CH 2 N-), 2.67 (s, 3H, -NCH 3 ), 2.86-3.05 (m, 2H, -CH 2 CH 2 N- ), 3.47-3.67 (m, 4H, -N CH 2 CH 2 O), 3.74-3.75 (m, 4H, -NCH 2 CH 2 O), 4.27 (s, 2H, Ar-CH 2- ), 4.45 (s, 1H, Ar-CH-), 7.12-7.17 (m, 1H, Ar-H), 7.23-7.28 (m, 1H, Ar-H), 7.37-7.41 (m , 3H, Ar-H), 7.42-7.50 (m, 2H, Ar-H), 7.65-7.71 (q, J = 8.0 Hz, 1H, Ar-H).

実施例 50
N-メチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-50）塩酸塩の調製
N-メチル-N-ベンジル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン（VI-50）の塩酸塩0.83gを得る。収率は80.9%。Mp=201.5-202.8℃， MS(m/z): 271.2[M+1]+。 Example 50
Preparation of N-methyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-50) hydrochloride
N-methyl-N-benzyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) dissolved in methanol (20 mL) at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 0.83 g of hydrochloride of N-methyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine (VI-50) is obtained. Yield 80.9%. Mp = 201.5-202.8 ° C, MS (m / z): 271.2 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.40-2.68 (m, 2H, -CH 2 CH2N-), 2.65 (s, 3H, -NCH3), 2.86-3.00 (m, 2H, -CH2 CH 2 N-), 3.47-3.55 (m, 4H, -NCH 2 CH2O), 3.74-3.75 (m, 4H, -NCH2 CH 2 O), 4.45 (s, 1H, Ar-CH-), 7.12-7.15 (m, 1H, Ar-H), 7.23-7.28 (m, 1H, Ar-H), 7.65-7.71 (q, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.40-2.68 (m, 2H, -CH 2 CH 2 N-), 2.65 (s, 3H, -NCH 3 ), 2.86-3.00 (m, 2H, -CH 2 CH 2 N- ), 3.47-3.55 (m, 4H, -N CH 2 CH 2 O), 3.74-3.75 (m, 4H, -NCH 2 CH 2 O), 4.45 (s, 1H, Ar-CH-), 7.12-7.15 (m, 1H, Ar-H), 7.23-7.28 (m, 1H, Ar-H), 7.65-7.71 (q, J = 8.0 Hz, 1H, Ar-H).

実施例 51
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-ベンジルピペラジニル)-プロピルアミン（VI-51）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、N-ベンジルピペラジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-ベンジルピペラジニル)-プロピルアミン（VI-51）の塩酸塩（白色固体）1.72 gを得る。収率は42.0%。Mp= 238.5-241.9℃， MS(m/z):407.2[M+1]+。 Example 51
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4-benzylpiperazinyl) -propylamine (VI-51) hydrochloride
N, N-dimethyl-3- (3,4-dichlorophenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operate in General Synthesis Method 4, and after the reaction, add N-benzylpiperazine (24 mmol) and potassium carbonate (8 mmol), react in General Synthesis Method 4, and then react with N, N-dimethyl-3- (3,4-dichlorophenyl) 1.72 g of hydrochloride (white solid) of -3- (4-benzylpiperazinyl) -propylamine (VI-51) is obtained. Yield 42.0%. Mp = 238.5-241.9 ° C., MS (m / z): 407.2 [M + 1] + .

1H NMR (DMSO-d6): δ: 2.31-2.62 (m, 2H, -CHCH 2 CH2N-), 2.71 (s, 6H, N(CH3)2), 2.79-2.81 (m, 2H, -CHCH2 CH 2 N-), 2.97-3.01 (m, 2H, -NCH2CH2N-), 3.33 (s, 6H, -NCH2CH2N-), 4.33 (s, 2H, Ar-CH2-), 4.42 (m, 1H, Ar-CH-), 7.41-7.46 (m, 3H, Ar-H), 7.49-7.51 (d, J=8.0Hz, 1H, Ar-H), 7.60-7.62 (m, 2H, Ar-H), 7.69-7.71 (d, J=8.4Hz, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 10.82 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 2.31-2.62 (m, 2H, -CH CH 2 CH 2 N-), 2.71 (s, 6H, N (CH 3 ) 2 ), 2.79-2.81 (m, 2H, -CHCH 2 CH 2 N-), 2.97-3.01 (m, 2H, -NCH 2 CH 2 N-), 3.33 (s, 6H, -NCH 2 CH 2 N-), 4.33 (s, 2H, Ar -CH 2- ), 4.42 (m, 1H, Ar-CH-), 7.41-7.46 (m, 3H, Ar-H), 7.49-7.51 (d, J = 8.0Hz, 1H, Ar-H), 7.60 -7.62 (m, 2H, Ar-H), 7.69-7.71 (d, J = 8.4Hz, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 10.82 (br, 1H, HCl, + D 2 O disappeared).

実施例 52
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-(3-(トリフルオロメチル)フェニル)ピペラジニル)-プロピルアミン（VI-52）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、4-(3-(トリフルオロメチル)フェニル)ピペラジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-(3-(トリフルオロメチル)フェニル)ピペラジニル)-プロピルアミン（VI-52）の塩酸塩（白色固体）1.82 gを得る。収率は40.2%。Mp= 245.6-248.2℃， MS(m/z):460.1[M+1]+。 Example 52
Preparation of N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4- (3- (trifluoromethyl) phenyl) piperazinyl) -propylamine (VI-52) hydrochloride
N, N-dimethyl-3- (3,4-dichlorophenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), Operate according to General Synthesis Method 4, and after the reaction, add 4- (3- (trifluoromethyl) phenyl) piperazine (24 mmol) and potassium carbonate (8 mmol), and react with General Synthesis Method 4, to obtain N, N-dimethyl- 1.82 g of hydrochloride salt (white solid) of 3- (3,4-dichlorophenyl) -3- (4- (3- (trifluoromethyl) phenyl) piperazinyl) -propylamine (VI-52) is obtained. Yield 40.2%. Mp = 245.6-248.2 ° C, MS (m / z): 460.1 [M + 1] + .

1H NMR (DMSO-d6)+D2O: δ: 2.63-2.68 (m, 2H, -CHCH 2 CH2N-), 2.74 (s, 6H, N(CH3)2), 2.97-3.05 (m, 2H, -CHCH2 CH 2 N-), 3.07-3.27 (m, 4H, -NCH2CH2N-), 3.50 (s, 4H, -NCH2CH2N-), 4.46-4.48 (d, J=8.8Hz, 1H, Ar-CH-), 7.12-7.22 (m, 3H, Ar-H), 7.42-7.46 (t, J=8.0Hz, 1H, Ar-H), 7.57-7.60 (q, J=1.6Hz, 1H, Ar-H), 7.74-7.76 (d, J=8.0Hz, 1H, Ar-H), 7.87-7.88 (d, J=1.6Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.63-2.68 (m, 2H, -CH CH 2 CH 2 N-), 2.74 (s, 6H, N (CH 3 ) 2 ), 2.97- 3.05 (m, 2H, -CHCH 2 CH 2 N-), 3.07-3.27 (m, 4H, -NCH 2 CH 2 N-), 3.50 (s, 4H, -NCH 2 CH 2 N-), 4.46-4.48 (d, J = 8.8Hz, 1H, Ar-CH-), 7.12-7.22 (m, 3H, Ar-H), 7.42-7.46 (t, J = 8.0Hz, 1H, Ar-H), 7.57-7.60 (q, J = 1.6Hz, 1H, Ar-H), 7.74-7.76 (d, J = 8.0Hz, 1H, Ar-H), 7.87-7.88 (d, J = 1.6Hz, 1H, Ar-H) .

実施例 53
N-メチル-N-ベンジル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジン-イル-プロピルアミン（VI-53）塩酸塩の調製
1,2-ベンゾジオキソール（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、3-クロロプロピオン酸クロライド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、3-クロロ-1-(1,2-ベンゾジオキソール-4-イル)-アセトン 9.5g（白色固体）を得る。収率は90.0%。MS(m/z): 213.0[M+1]+。 Example 53
Preparation of N-methyl-N-benzyl-3- (1,2-benzodioxol-4-yl) -3-piperidin-yl-propylamine (VI-53) hydrochloride
Dissolve 1,2-benzodioxole (0.05 mol) in dichloromethane (30 mL), control the internal temperature to 5 ° C or lower, add AlCl 3 (0.10 mol) in portions, and add 3-chloropropionic acid chloride (0.055 mol). ) And is operated by Method A of General Synthesis Method 1 to obtain 9.5 g (white solid) of 3-chloro-1- (1,2-benzodioxol-4-yl) -acetone. Yield 90.0%. MS (m / z): 213.0 [M + 1] + .

該中間体（0.03mol）、N-メチルベンジルアミン塩酸塩（0.03mol）、ジイソプロピルエチルアミン (0.10mol) をアセトニトリル（60mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物5.99gを得る。収率は60.0%。MS(m/z): 298.1[M+1]+。 The intermediate (0.03 mol), N-methylbenzylamine hydrochloride (0.03 mol), diisopropylethylamine (0.10 mol) were dissolved in acetonitrile (60 mL) and operated by General Synthesis Method 2, Method B to give a white solid product, 5.99. get g. Yield 60.0%. MS (m / z): 298.1 [M + 1] + .

前記生成物（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.88gを得る。収率は85.9%。MS(m/z): 300.2[M+1]+。 The product (10 mmol), sodium borohydride (10 mmol) is operated in methanol (50 mL) according to general synthesis method 3 to obtain 2.88 g of a white solid. Yield 85.9%. MS (m / z): 300.2 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン（VI-53）の塩酸塩（白色固体）1.49gを得る。収率は42.5%。Mp= 285.6-288.9℃， MS(m/z): 367.4[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, piperidine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine (VI-53) hydrochloric acid 1.49 g of salt (white solid) are obtained. Yield 42.5%. Mp = 285.6-288.9 ° C, MS (m / z): 367.4 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.49-1.55 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.35-2.41 (m, 2H, -CH 2 CH2N-), 2.68 (s, 3H, -NCH3), 2.78-2.83 (m, 2H, -CH2 CH 2 N-), 3.02-3.09 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.19 (s, 2H, Ar-CH2-), 4.27-4.29 (d, J=8.4Hz, 1H, Ar-CH-), 6.12 (s, 2H, -OCH2O-), 7.25-7.33 (m, 6H, Ar-H), 7.55-7.58 (d, J=8.4Hz, 1H, Ar-H), 7.64-7.65 (d, J=2.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.49-1.55 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.35-2.41 (m, 2H, -CH 2 CH 2 N-), 2.68 (s, 3H, -NCH 3 ), 2.78-2.83 (m, 2H, -CH 2 CH 2 N-), 3.02-3.09 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.19 (s, 2H, Ar-CH 2- ), 4.27-4.29 (d, J = 8.4Hz, 1H, Ar-CH-), 6.12 (s, 2H, -OCH 2 O -), 7.25-7.33 (m, 6H, Ar-H), 7.55-7.58 (d, J = 8.4Hz, 1H, Ar-H), 7.64-7.65 (d, J = 2.0Hz, 1H, Ar-H ).

実施例 54
N-メチル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン（VI-54）塩酸塩の調製
N-メチル-N-ベンジル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン（VI-54）の塩酸塩0.84gを得る。収率は80.5%。Mp=189.3-192.4℃， MS(m/z): 277.2[M+1]+。 Example 54
Preparation of N-methyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine (VI-54) hydrochloride
N-methyl-N-benzyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) in methanol (20 mL) Dissolve in, add hydrogen at room temperature and normal pressure, react for 2 hours, remove palladium on carbon by filtration, concentrate the filtrate, and obtain a white solid. After recrystallization from absolute ethanol (10 mL), 0.84 g of N-methyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine (VI-54) hydrochloride is obtained. Yield 80.5%. Mp = 189.3-192.4 ° C, MS (m / z): 277.2 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.53-1.58 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.35-2.40 (m, 2H, -CH 2 CH2N-), 2.65-2.71 (m, 2H, -CH2 CH 2 N-), 3.03-3.09 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 3.26 (s, 3H, -NCH3), 4.28-4.31 (d, J=8.0Hz, 1H, Ar-CH-), 6.10 (s, 2H, -OCH2O-), 7.23-7.25 (d, J=8.4Hz, 1H, Ar-H), 7.58-7.61 (d, J=8.4Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.53-1.58 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.35-2.40 (m, 2H, -CH 2 CH 2 N-), 2.65-2.71 (m, 2H, -CH 2 CH 2 N-), 3.03-3.09 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 3.26 (s , 3H, -NCH 3 ), 4.28-4.31 (d, J = 8.0Hz, 1H, Ar-CH-), 6.10 (s, 2H, -OCH 2 O-), 7.23-7.25 (d, J = 8.4Hz , 1H, Ar-H), 7.58-7.61 (d, J = 8.4 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H).

実施例 55
N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-55）塩酸塩の調製
1,2-ジメトキシベンゼン（0.05mol）をジクロロメタン(30mL)に溶かし、内温5℃以下に制御し、AlCl3(0.10mol)を分割的に加え、3-クロロプロピオン酸クロライド（0.055mol）を滴下し、一般合成法一の方法Aで操作し、3-クロロ-1-(3,4-ジメトキシフェニル)-アセトン 10.3g（白色固体）を得る。収率は90.0%。MS(m/z): 229.0[M+1]+。 Example 55
Preparation of N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-55) hydrochloride
Dissolve 1,2-dimethoxybenzene (0.05 mol) in dichloromethane (30 mL), control the internal temperature to 5 ° C or lower, add AlCl 3 (0.10 mol) in portions, and add 3-chloropropionic acid chloride (0.055 mol). Add dropwise and operate in Method A of General Synthesis Method 1 to obtain 10.3 g (white solid) of 3-chloro-1- (3,4-dimethoxyphenyl) -acetone. Yield 90.0%. MS (m / z): 229.0 [M + 1] < +>.

該中間体（0.03mol）、ジメチルアミン水溶液（0.15mol）を無水エタノール（50mL）に溶かし、一般合成法二の方法Aで操作し、白色固体生成物7.78gを得る。収率は95.0%。MS(m/z): 238.2[M+1]+。 The intermediate (0.03 mol) and dimethylamine aqueous solution (0.15 mol) are dissolved in absolute ethanol (50 mL) and operated by Method A of General Synthesis Method 2 to obtain 7.78 g of a white solid product. Yield 95.0%. MS (m / z): 238.2 [M + 1] < +>.

前記白色固体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.2gを得る。収率は80.0%。MS(m/z): 240.2[M+1]+。 The white solid (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.2 g of a white solid. Yield 80.0%. MS (m / z): 240.2 [M + 1] < +>.

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-55）の塩酸塩（白色固体）1.52gを得る。収率は50.0%。Mp= 232.5-234.8℃， MS(m/z): 309.3[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.52 g of hydrochloride (white solid) of N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-55) obtain. Yield 50.0%. Mp = 232.5-234.8 ° C., MS (m / z): 309.3 [M + 1] + .

1H NMR (DMSO-d6): δ: 1.87-1.98 (m, 2H, -CH 2 CH2N-), 2.32-2.45 (m, 2H, -CH2 CH 2 N-), 2.70 (s, 6H, N(CH3)2), 2.73-2.80 (m, 4H, -NCH 2 CH2O), 3.60-3.64 (m, 4H, -NCH2 CH 2 O), 3.71 (s, 6H, -OCH3), 3.78-3.81 (t, J=8.0Hz, 1H, Ar-CH-), 7.28-7.31 (dd, J1=1.6Hz, J2=8.0Hz, 1H, Ar-H), 7.36-7.38 (dd, J1=1.6Hz, J2=8.0Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 10.60 (br, 1H, HCl, +D2O消失)。 1 H NMR (DMSO-d 6 ): δ: 1.87-1.98 (m, 2H, -CH 2 CH 2 N-), 2.32-2.45 (m, 2H, -CH 2 CH 2 N-), 2.70 (s, 6H, N (CH 3 ) 2 ), 2.73-2.80 (m, 4H, -N CH 2 CH 2 O), 3.60-3.64 (m, 4H, -NCH 2 CH 2 O), 3.71 (s, 6H,- OCH 3 ), 3.78-3.81 (t, J = 8.0Hz, 1H, Ar-CH-), 7.28-7.31 (dd, J 1 = 1.6Hz, J 2 = 8.0Hz, 1H, Ar-H), 7.36- 7.38 (dd, J 1 = 1.6 Hz, J 2 = 8.0 Hz, 1H, Ar—H), 7.63 (s, 1H, Ar—H), 10.60 (br, 1H, HCl, + D 2 O disappearance).

実施例 56
N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-56）塩酸塩の調製
3-クロロ-1-(3,4-ジメトキシフェニル)-アセトン（0.02mol）、N-メチルベンジルアミン塩酸塩（0.02mol）、ジイソプロピルエチルアミン(0.06mol) をアセトニトリル（60mL）に溶かし、一般合成法二の方法Bで操作し、白色固体生成物4.62gを得る。収率は60.0%。MS(m/z): 314.2[M+1]+。 Example 56
Preparation of N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-56) hydrochloride
3-chloro-1- (3,4-dimethoxyphenyl) -acetone (0.02mol), N-methylbenzylamine hydrochloride (0.02mol), diisopropylethylamine (0.06mol) dissolved in acetonitrile (60mL) Operate in the second method B to obtain 4.62 g of white solid product. Yield 60.0%. MS (m / z): 314.2 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体3.29gを得る。収率は85.0%。MS(m/z): 316.1[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 3.29 g of a white solid. Yield 85.0%. MS (m / z): 316.1 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-56）の塩酸塩（白色固体）1.67gを得る。収率は45.8%。Mp= 278.5-281.3℃， MS(m/z): 385.4[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-56) hydrochloride (white solid) 1.67 get g. Yield 45.8%. Mp = 278.5-281.3 ° C., MS (m / z): 385.4 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 2.25-2.34 (m, 2H, -CH 2 CH2N-), 2.41-2.52 (m, 2H, -NCH 2 CH2O), 2.68 (s, 3H, -NCH3), 2.81-2.88 (m, 2H, -CH2 CH 2 N-), 3.01-3.05 (m, 2H, -NCH 2 CH2O), 3.60-3.65 (m, 4H, -NCH2 CH 2 O), 4.05 (s, 2H, Ar-CH2-), 4.21 (s, 6H, -OCH3), 4.29-4.31 (d, J=6.4Hz, 1H, Ar-CH-), 7.12-7.14 (d, J=8.4Hz, 1H, Ar-H), 7.19-7.22 (d, J=8.0Hz, 1H, Ar-H), 7.34-7.38 (m, 6H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.25-2.34 (m, 2H, -CH 2 CH 2 N-), 2.41-2.52 (m, 2H, -N CH 2 CH 2 O), 2.68 (s, 3H, -NCH 3 ), 2.81-2.88 (m, 2H, -CH 2 CH 2 N- ), 3.01-3.05 (m, 2H, -N CH 2 CH 2 O), 3.60-3.65 (m , 4H, -NCH 2 CH 2 O), 4.05 (s, 2H, Ar-CH 2- ), 4.21 (s, 6H, -OCH 3 ), 4.29-4.31 (d, J = 6.4Hz, 1H, Ar- CH-), 7.12-7.14 (d, J = 8.4Hz, 1H, Ar-H), 7.19-7.22 (d, J = 8.0Hz, 1H, Ar-H), 7.34-7.38 (m, 6H, Ar- H).

実施例 57
N-メチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-57）塩酸塩の調製
N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン（VI-57）の塩酸塩0.84gを得る。収率は76.2%。Mp=200.2-203.4℃， MS(m/z): 295.2[M+1]+。 Example 57
Preparation of N-methyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-57) hydrochloride
N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) was dissolved in methanol (20 mL), and at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 0.84 g of N-methyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine (VI-57) hydrochloride is obtained. Yield 76.2%. Mp = 200.2-203.4 ° C, MS (m / z): 295.2 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 2.31-2.37 (m, 2H, -CH 2 CH2N-), 2.65-2.69 (m, 2H, -CH2 CH 2 N-), 2.87-2.91 (m, 4H, -NCH 2 CH2O), 3.23 (s, 3H, -NCH3), 3.61-3.65 (m, 4H, -NCH2 CH 2 O), 4.19 (s, 6H, -OCH3), 4.26-4.28 (d, J=8.0Hz, 1H, Ar-CH-), 7.27-7.29 (d, J=8.4Hz, 1H, Ar-H), 7.58-7.61 (d, J=8.8Hz, 1H, Ar-H), 7.71 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.31-2.37 (m, 2H, -CH 2 CH 2 N-), 2.65-2.69 (m, 2H, -CH 2 CH 2 N- ), 2.87-2.91 (m, 4H, -N CH 2 CH 2 O), 3.23 (s, 3H, -NCH 3 ), 3.61-3.65 (m, 4H, -NCH 2 CH 2 O), 4.19 (s, 6H, -OCH 3 ), 4.26-4.28 (d, J = 8.0Hz, 1H, Ar-CH-), 7.27-7.29 (d, J = 8.4Hz, 1H, Ar-H), 7.58-7.61 (d, J = 8.8Hz, 1H, Ar-H), 7.71 (s, 1H, Ar-H).

実施例 58
N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-58）塩酸塩の調製
N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-58）の塩酸塩（白色固体）1.27gを得る。収率は42.0%。Mp=220.3.5-224.0℃， MS(m/z): 307.2[M+1]+。 Example 58
Preparation of N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine (VI-58) hydrochloride
N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL). After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added, and the reaction was performed according to General Synthesis Method 4. N, N-dimethyl-3- (3,4-dimethoxyphenyl)- 1.27 g of hydrochloride (white solid) of 3-piperidinyl-propylamine (VI-58) is obtained. Yield 42.0%. Mp = 220.3.5-224.0 ° C, MS (m / z): 307.2 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.52-1.60 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.02-2.10 (m, 2H, -CH 2 CH2N-), 2.29-2.36 (m, 2H, -CH2 CH 2 N-), 2.70 (s, 6H, N(CH3)2), 3.10-3.15 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 3.67 (s, 6H, -OCH3), 3.75-3.78 (t, J=8.4Hz, 1H, Ar-CH-), 7.21-7.23 (d, J=8.4Hz, 1H, Ar-H), 7.50-7.53 (d, J=8.8Hz, 1H, Ar-H), 7.69 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.52-1.60 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.02-2.10 (m, 2H, -CH 2 CH 2 N-), 2.29-2.36 (m, 2H, -CH 2 CH 2 N-), 2.70 (s, 6H, N (CH 3 ) 2 ), 3.10-3.15 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 3.67 (s, 6H, -OCH 3 ), 3.75-3.78 (t, J = 8.4Hz, 1H, Ar-CH-), 7.21-7.23 (d, J = 8.4 Hz, 1H, Ar-H), 7.50-7.53 (d, J = 8.8 Hz, 1H, Ar-H), 7.69 (s, 1H, Ar-H).

実施例 59
N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-59）塩酸塩の調製
N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ヒドロキシ-プロピルアミン塩酸塩（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、ピペリジン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-59）の塩酸塩（白色固体）1.56gを得る。収率は43.0%。Mp=256.6-258.9℃， MS(m/z): 383.3[M+1]+。 Example 59
Preparation of N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine (VI-59) hydrochloride
N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-hydroxy-propylamine hydrochloride (8 mmol), triethylamine (9.6 mmol), paratoluenesulfonyl chloride (8.8 mmol) in acetonitrile (30 mL) After the reaction, piperidine (24 mmol) and potassium carbonate (8 mmol) were added and reacted according to General Synthesis Method 4. N-methyl-N-benzyl-3- (3,4- 1.56 g of hydrochloride (white solid) of dimethoxyphenyl) -3-piperidinyl-propylamine (VI-59) is obtained. Yield 43.0%. Mp = 256.6-258.9 ° C, MS (m / z): 383.3 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.48-1.53 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.30-2.36 (m, 2H, -CH 2 CH2N-), 2.69 (s, 3H, -NCH3), 2.80-2.85 (m, 2H, -CH2 CH 2 N-), 3.11-3.16 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 4.19 (s, 2H, Ar-CH2-), 4.25 (s, 6H, -OCH3), 4.29-4.31 (d, J=7.2Hz, 1H, Ar-CH-), 7.13-7.16 (d, J=8.4Hz, 1H, Ar-H), 7.22-7.25 (d, J=8.0Hz, 1H, Ar-H), 7.35-7.39 (m, 6H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.48-1.53 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.30-2.36 (m, 2H, -CH 2 CH 2 N-), 2.69 (s, 3H, -NCH 3 ), 2.80-2.85 (m, 2H, -CH 2 CH 2 N- ), 3.11-3.16 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 4.19 (s, 2H, Ar-CH 2- ), 4.25 (s, 6H, -OCH 3 ), 4.29-4.31 (d, J = 7.2Hz, 1H, Ar-CH-) , 7.13-7.16 (d, J = 8.4Hz, 1H, Ar-H), 7.22-7.25 (d, J = 8.0Hz, 1H, Ar-H), 7.35-7.39 (m, 6H, Ar-H).

実施例 60
N-メチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-60）塩酸塩の調製
N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン塩酸塩（3mmol）、5％パラジウム炭素（0.1g）をメタノール（20mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン（VI-60）の塩酸塩0.94gを得る。収率は85.7%。Mp=195.2-197.8℃， MS(m/z): 293.3[M+1]+。 Example 60
Preparation of N-methyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine (VI-60) hydrochloride
N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine hydrochloride (3 mmol), 5% palladium on carbon (0.1 g) was dissolved in methanol (20 mL), and at room temperature and normal pressure Add hydrogen and react for 2 hours to remove palladium on carbon and concentrate the filtrate to give a white solid. After recrystallization from absolute ethanol (10 mL), 0.94 g of N-methyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine (VI-60) hydrochloride is obtained. Yield 85.7%. Mp = 195.2-197.8 ° C, MS (m / z): 293.3 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 1.45-1.50 (m, 6H, -NCH2 CH 2 CH 2 CH 2 CH2N-), 2.30-2.34 (m, 2H, -CH 2 CH2N-), 2.67-2.72 (m, 2H, -CH2 CH 2 N-), 3.00-3.07 (m, 4H, -NCH 2 CH2CH2CH2 CH 2 N-), 3.28 (s, 3H, -NCH3), 4.21 (s, 6H, -OCH3), 4.27-4.29 (d, J=8.0Hz, 1H, Ar-CH-), 7.23-7.25 (d, J=8.4Hz, 1H, Ar-H), 7.55-7.58 (d, J=8.8Hz, 1H, Ar-H), 7.69 (s, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 1.45-1.50 (m, 6H, -NCH 2 CH 2 CH 2 CH 2 CH 2 N-), 2.30-2.34 (m, 2H, -CH 2 CH 2 N-), 2.67-2.72 (m, 2H, -CH 2 CH 2 N- ), 3.00-3.07 (m, 4H, -N CH 2 CH 2 CH 2 CH 2 CH 2 N-), 3.28 (s , 3H, -NCH 3 ), 4.21 (s, 6H, -OCH 3 ), 4.27-4.29 (d, J = 8.0Hz, 1H, Ar-CH-), 7.23-7.25 (d, J = 8.4Hz, 1H , Ar-H), 7.55-7.58 (d, J = 8.8 Hz, 1H, Ar-H), 7.69 (s, 1H, Ar-H).

実施例 61
N,N-ジメチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-61）塩酸塩の調製
2-アセチルチオフェン(0.05mol)、ジメチルアミン塩酸塩（0.055mol）及びパラホルムアルデヒド（0.065mol）を95％エタノール（20mL）に溶かし、濃塩酸（0.2mL）を加え、一般合成法二の方法Cで操作し、白色固体7.66gを得る。収率は70.0％。MS(m/z): 184.1[M+1]+。 Example 61
Preparation of N, N-dimethyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-61) hydrochloride
Dissolve 2-acetylthiophene (0.05 mol), dimethylamine hydrochloride (0.055 mol) and paraformaldehyde (0.065 mol) in 95% ethanol (20 mL), add concentrated hydrochloric acid (0.2 mL), and add Method C of General Synthesis Method II. To obtain 7.66 g of a white solid. Yield is 70.0%. MS (m / z): 184.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体1.99gを得る。収率は90.2%。MS(m/z): 186.0[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 1.99 g of a white solid. Yield 90.2%. MS (m / z): 186.0 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N,N-ジメチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-61）の塩酸塩（白色固体）1.20gを得る。収率は46.2%。Mp= 195.0-197.3℃， MS(m/z): 255.1[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ) And reacted in General Synthesis Method 4 to obtain 1.20 g of hydrochloride (white solid) of N, N-dimethyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-61) . Yield 46.2%. Mp = 195.0-197.3 ° C, MS (m / z): 255.1 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 2.05-2.09 (m, 1H, -CH 2 CH2N-), 2.23-2.29 (m, 4H, -NCH 2 CH2O), 2.32-2.36 (m, 1H, -CH 2 CH2N-), 2.69 (s, 6H, N(CH3)2), 2.78-2.81 (m, 2H, -CH2 CH 2 N-), 3.48-3.52 (m, 4H, -NCH2 CH 2 O), 3.59-3.61 (t, J=7.2Hz, 1H, Ar-CH-), 7.02-7.05 (d, J=8.8Hz, 1H, Ar-H), 7.15-7.18 (m, 1H, Ar-H), 7.29-7.32 (d, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.05-2.09 (m, 1H, -CH 2 CH 2 N-), 2.23-2.29 (m, 4H, -N CH 2 CH 2 O), 2.32-2.36 (m, 1H, -CH 2 CH 2 N-), 2.69 (s, 6H, N (CH 3 ) 2 ), 2.78-2.81 (m, 2H, -CH 2 CH 2 N-), 3.48- 3.52 (m, 4H, -NCH 2 CH 2 O), 3.59-3.61 (t, J = 7.2Hz, 1H, Ar-CH-), 7.02-7.05 (d, J = 8.8Hz, 1H, Ar-H) , 7.15-7.18 (m, 1H, Ar-H), 7.29-7.32 (d, J = 8.0Hz, 1H, Ar-H).

実施例 62
N-メチル-N-ベンジル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-62）塩酸塩の調製
2-アセチルチオフェン(20mmol)、N-メチルアニリン塩酸塩（22mmol）及びパラホルムアルデヒド（26mmol）を95％エタノール（10mL）に溶かし、濃塩酸（0.05mL）を加え、一般合成法二の方法Cで操作し、白色固体4.48gを得る。収率は76.0％。MS(m/z): 260.1[M+1]+。 Example 62
Preparation of N-methyl-N-benzyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-62) hydrochloride
2-acetylthiophene (20 mmol), N-methylaniline hydrochloride (22 mmol) and paraformaldehyde (26 mmol) are dissolved in 95% ethanol (10 mL), concentrated hydrochloric acid (0.05 mL) is added, and General Synthetic Method II Method C is used. Operate to obtain 4.48 g of white solid. Yield 76.0%. MS (m / z): 260.1 [M + 1] + .

前記中間体（10mmol）、水酸化ホウ素ナトリウム（10mmol）をメタノール（50mL）中で、一般合成法三で操作し、白色固体2.67gを得る。収率は90.0%。MS(m/z): 262.0[M+1]+。 The intermediate (10 mmol) and sodium borohydride (10 mmol) are operated in methanol (50 mL) according to General Synthesis Method 3 to obtain 2.67 g of a white solid. Yield 90.0%. MS (m / z): 262.0 [M + 1] + .

更に、生成物（8mmol）、トリエチルアミン（9.6mmol）、塩化パラトルエンスルホニル（8.8mmol）をアセトニトリル（30mL）に溶かし、一般合成法四で操作し、反応後、モルホリン（24mmol）、炭酸カリウム（8mmol）を加え、一般合成法四で反応させ、N-メチル-N-ベンジル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-62）の塩酸塩（白色固体）1.54 gを得る。収率は48.0%。Mp= 220.8-224.0℃， MS(m/z): 331.2[M+1]+。 Further, the product (8 mmol), triethylamine (9.6 mmol), p-toluenesulfonyl chloride (8.8 mmol) were dissolved in acetonitrile (30 mL), and operated according to General Synthesis Method 4. After the reaction, morpholine (24 mmol), potassium carbonate (8 mmol) ), And reacted according to general synthesis method 4. Hydrochloric acid salt of N-methyl-N-benzyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-62) (white solid) 1.54 g Get. Yield 48.0%. Mp = 220.8-224.0 ° C, MS (m / z): 331.2 [M + 1] + .

1H NMR (DMSO-d6) +D2O: δ: 2.11-2.16 (m, 2H, -CH 2 CH2N-), 2.22-2.30 (m, 4H, -NCH 2 CH2O), 2.69 (s, 3H, -NCH3), 2.78-2.82 (m, 2H, -CH2 CH 2 N-), 3.59-3.62 (m, 4H, -NCH2 CH 2 O), 4.23 (s, 2H, Ar-CH2-), 4.30-4.32 (t, J=7.2Hz, 1H, Ar-CH-), 7.00-7.03 (d, J=8.8Hz, 1H, Ar-H), 7.14-7.17 (m, 1H, Ar-H), 7.25-7.30 (m, 5H, Ar-H), 7.33-7.35 (d, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.11-2.16 (m, 2H, -CH 2 CH 2 N-), 2.22-2.30 (m, 4H, -N CH 2 CH 2 O), 2.69 (s, 3H, -NCH 3 ), 2.78-2.82 (m, 2H, -CH 2 CH 2 N-), 3.59-3.62 (m, 4H, -NCH 2 CH 2 O), 4.23 (s, 2H, Ar-CH 2- ), 4.30-4.32 (t, J = 7.2Hz, 1H, Ar-CH-), 7.00-7.03 (d, J = 8.8Hz, 1H, Ar-H), 7.14-7.17 (m, 1H, Ar-H), 7.25-7.30 (m, 5H, Ar-H), 7.33-7.35 (d, J = 8.0 Hz, 1H, Ar-H).

実施例 63
N-メチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-63）塩酸塩の調製
N-メチル-N-ベンジル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン塩酸塩（5mmol）、5％パラジウム炭素（0.2g）をメタノール（30mL）に溶かし、室温常圧下で、水素を加え、2時間反応させ、パラジウム炭素をろ過除去し、ろ液濃縮後、白色固体を得る。無水エタノール（10mL）再結晶後、N-メチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン（VI-63）の塩酸塩1.10gを得る。収率は70.2%。Mp= 151.2-154.3℃， MS(m/z): 241.0[M+1]+。 Example 63
Preparation of N-methyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-63) hydrochloride
N-methyl-N-benzyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine hydrochloride (5 mmol), 5% palladium on carbon (0.2 g) dissolved in methanol (30 mL) at room temperature and normal pressure Hydrogen is added and reacted for 2 hours, palladium carbon is removed by filtration, and the filtrate is concentrated to obtain a white solid. After recrystallization from absolute ethanol (10 mL), 1.10 g of N-methyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine (VI-63) hydrochloride is obtained. Yield 70.2%. Mp = 151.2-154.3 ° C., MS (m / z): 241.0 [M + 1] + .

1H NMR (DMSO-d6)＋D2O: δ: 2.12-2.25 (m, 2H, -CH 2 CH2N-), 2.35-2.40 (m, 4H, -NCH 2 CH2O), 2.80-2.88 (m, 2H, -CH2 CH 2 N-), 3.45 (s, 3H, N-CH3), 3.58-3.66 (m, 4H, -NCH2 CH 2 O), 3.77-3.79 (t, J=7.2Hz, 1H, Ar-CH-), 7.05-7.07 (d, J=8.8Hz, 1H, Ar-H), 7.12-7.15 (m, 1H, Ar-H), 7.28-7.31 (d, J=8.0Hz, 1H, Ar-H)。 1 H NMR (DMSO-d 6 ) + D 2 O: δ: 2.12-2.25 (m, 2H, -CH 2 CH 2 N-), 2.35-2.40 (m, 4H, -N CH 2 CH 2 O), 2.80 -2.88 (m, 2H, -CH 2 CH 2 N-), 3.45 (s, 3H, N-CH 3 ), 3.58-3.66 (m, 4H, -NCH 2 CH 2 O), 3.77-3.79 (t, J = 7.2Hz, 1H, Ar-CH-), 7.05-7.07 (d, J = 8.8Hz, 1H, Ar-H), 7.12-7.15 (m, 1H, Ar-H), 7.28-7.31 (d, J = 8.0Hz, 1H, Ar-H).

実施例 64
錠剤：実施例1-63の化合物 10mg
スクロース 150mg
コーンスターチ 38mg
ステアリン酸カルシウム 2mg
調製方法：活性成分をスクロース、コーンスターチと混合し、水を加えて湿らせ、均一に攪拌し、乾燥し、粉砕してふるいにかけ、ステアリン酸カルシウムを加え、均一に混ぜ、打錠を行う。各錠の重さは200 mgで、活性成分の含有量は10mgである。 Example 64
Tablet: 10 mg of the compound of Example 1-63
Sucrose 150mg
Corn starch 38mg
Calcium stearate 2mg
Preparation method: The active ingredient is mixed with sucrose and corn starch, moistened with water, uniformly stirred, dried, crushed and sieved, calcium stearate is added, mixed uniformly, and tableted. Each tablet weighs 200 mg and the active ingredient content is 10 mg.

実施例 65
注射剤：実施例1-63の化合物 20mg
注射用水 80mg
調製方法：活性成分を注射用水に溶解し、均一に混ぜ、濾過し、得られた溶液を無菌条件でアンプルに分注する。各アンプルは10mgで、活性成分の含有量は2mg/lアンプルである。 Example 65
Injection: 20 mg of the compound of Example 1-63
Water for injection 80mg
Preparation method: The active ingredient is dissolved in water for injection, mixed uniformly, filtered, and the resulting solution is dispensed into ampoules under aseptic conditions. Each ampoule is 10 mg and the active ingredient content is 2 mg / l ampoule.

実施例 66
化合物の抗うつ作用
一．化合物の5-セロトニン(5-HT)、ノルアドレナリン(NA)及びドーパミン(DA) 再取り込みに対する阻害作用：
細胞モノクローナル技術と放射リガンド結合実験の方法を用いてターゲットが明確な新化合物に対して体外スクリーニング研究を行う。この方法は相応の生物活性評価を客観的に正確に早く出すことができる。（Biochem Phearmacol 2008, 75(9): 1835-1847及びEur J Pharmacol, 2007, 576(1-3): 43-54）で紹介された研究方法を用いて化合物に対して体外スクリーニングを行う。また、有効的な5-HT、NA二重再取り込み阻害薬であるベンラファクシン(Venlafaxine)及び5-HT、NA、DA三重再取り込み阻害薬であるDOV 21947を陽性対照品として、発明する化合物の5-HT、NA及びDA再取り込みに対する阻害作用について研究する。方法は以下のとおりである。 Example 66
Antidepressant action of compounds Inhibitory effects of compounds on 5-serotonin (5-HT), noradrenaline (NA) and dopamine (DA) reuptake:
Conduct in vitro screening studies on new compounds with well-defined targets using cell monoclonal technology and radioligand binding experiments. This method enables objective and accurate assessment of biological activity quickly. In vitro screening is performed on compounds using the research method introduced in (Biochem Phearmacol 2008, 75 (9): 1835-1847 and Eur J Pharmacol, 2007, 576 (1-3): 43-54). In addition, the compound to invent as an effective 5-HT, NA double reuptake inhibitor Venlafaxine and 5-HT, NA, DA triple reuptake inhibitor DOV 21947 as positive control products To study the inhibitory effects of 5-HT, NA and DA on reuptake. The method is as follows.

1. 5-HTトランスポーター(hSERT)、NAトランスポーター(hNAT)及びDAトランスポーター(hDAT)安定細胞株の構築
pcDNA3.0-hSERT/hNAT/hDAT担体プラスミドによりHEK 293細胞をそれぞれトランスフェクションする。48時間トランスフェクションした後、G418選択性DMEM培養液を加えて細胞を培養する。3週後、希釈し続けることでG418抵抗性細胞が現れる。安定してトランスフェクションされた単クローン細胞を得て、再びG418を含む培養液で培養を増やし、5-HT/NA/DA により再取り込みして単クローン細胞上の5-HT/NA/DAトランスポーターの表現を実験検証する。最後に5-HT/NA/DAトランスポータータンパクが安定表現される安定細胞株を得る。 1. Construction of stable cell lines of 5-HT transporter (hSERT), NA transporter (hNAT) and DA transporter (hDAT)
HEK 293 cells are each transfected with pcDNA3.0-hSERT / hNAT / hDAT carrier plasmid. After 48 hours of transfection, the cells are cultured with G418-selective DMEM medium. After 3 weeks, G418 resistant cells appear by continuing to dilute. Obtain a stably transfected monoclonal cell, increase the culture again with medium containing G418, re-uptake with 5-HT / NA / DA, and recapture 5-HT / NA / DA trans Experimentally verify the expression of the porter. Finally, a stable cell line that stably expresses 5-HT / NA / DA transporter protein is obtained.

2. 5-HT/NA/DA再取り込み実験
測定される化合物、ベンラファクシン/DOV 21947(陽性薬)を、DMSOを用いてそれぞれ0.01 mol/Lまで溶解し、その後、脱イオン水で100μmol/Lまで希釈する。測定される化合物（又は陽性薬物）50μl、細胞430μlを取り反応試験管に入れ、30℃の水浴で10分インキュベー卜した後、再び放射性[3H]-5-HT/[3H]-NA /[3H]-DA 20μlをそれぞれ加え、測定される化合物（又は陽性薬物）の最終濃度を全て10μmol/Lにする。30℃の水浴で10分インキュベー卜した後、すぐに氷浴に移して反応を終了させる。24ウェルBRANDEL細胞サンプル収集器において、GF/Bガラス繊維濾紙で素早く吸引濾過し、氷冷のバッファー(50mM Tris, 5mM EDTA, pH 7.4)で三回洗浄し、濾紙を乾燥した後、0.5mlの遠心管に置き、500μlの脂溶性液体シンチレーションカクテルを加え、MicroBeta液体シンチレーションカウンターで放射強度を測定する。実験は総再取り込み管（空白対照）、非特異的再取り込み管（10μmol/L陽性薬）、サンプル再取り込み管（10μmol/L測定される化合物）に分ける。各濃度は平行管（parallel tubes）を測定し、三回の独立実験を行う。 2. 5-HT / NA / DA reuptake experiment Dissolve the compound to be measured, venlafaxine / DOV 21947 (positive drug) to 0.01 mol / L using DMSO, and then add 100 μmol / L with deionized water. Dilute to L. Take 50 μl of the compound to be measured (or positive drug) and 430 μl of cells, put them in a reaction tube, incubate in a water bath at 30 ° C. for 10 minutes, and again radioactive [ 3 H] -5-HT / [ 3 H] -NA Add 20 μl each of / [ 3 H] -DA to bring the final concentration of compound (or positive drug) to be measured to 10 μmol / L. Incubate in a 30 ° C water bath for 10 minutes, then immediately transfer to an ice bath to complete the reaction. In a 24-well BRANDEL cell sample collector, filter quickly with GF / B glass fiber filter, wash three times with ice-cold buffer (50 mM Tris, 5 mM EDTA, pH 7.4), dry the filter, and then add 0.5 ml Place in a centrifuge tube, add 500 μl of fat-soluble liquid scintillation cocktail and measure radiant intensity with a MicroBeta liquid scintillation counter. The experiment is divided into a total reuptake tube (blank control), a non-specific reuptake tube (10 μmol / L positive drug), and a sample reuptake tube (10 μmol / L measured compound). Each concentration is measured in parallel tubes and three independent experiments are performed.

以下の公式で各化合物の再取り込み阻害百分率を計算する：
再取り込み阻害率（I％）＝（総再取り込み管cpm−サンプル再取り込み管cpm）/（総再取り込み管cpm−非特異的再取り込み管cpm）×100% Calculate the percent reuptake inhibition for each compound with the following formula:
Reuptake inhibition rate (I%) = (total reuptake tube cpm−sample reuptake tube cpm) / (total reuptake tube cpm−non-specific reuptake tube cpm) × 100%

3. 結果：
同じ濃度条件(対照薬及び測定される薬物は共に0.1mmol/L)で、市販の抗うつ薬ベンラファクシン及び抗うつII相臨床化合物DOV 21947を陽性対照品とし，5-HT、NA及びDA再取り込みに対する阻害率の測定結果は表2に示す。 3. Result:
Commercially available antidepressant drug venlafaxine and antidepressant phase II clinical compound DOV 21947 under the same concentration conditions (both control drug and measured drug are 0.1 mmol / L), 5-HT, NA and DA The measurement results of the inhibition rate against reuptake are shown in Table 2.

Figure 2013530137
Figure 2013530137

実験結果は次のとおり：濃度が10μmol/Lであるとき、化合物VI-1、VI-2、VI-4、VI-6、VI-13、VI-16、VI-19、VI-22、VI-31、VI-36、VI-46は5-HT、NA及DA再取り込みに対して強い阻害活性を有し、その作用強度はベンラファクシン、DOV21947に相当する。   The experimental results are as follows: When the concentration is 10 μmol / L, compounds VI-1, VI-2, VI-4, VI-6, VI-13, VI-16, VI-19, VI-22, VI -31, VI-36, and VI-46 have strong inhibitory activity against 5-HT, NA and DA reuptake, and their action strengths correspond to venlafaxine and DOV21947.

二．化合物のin vivo抗うつ結果：
「学習性絶望試験」におけるマウス尾懸垂試験( tail suspension test )と、マウス強制水泳試験( forced swimming test )を採用し、ベンラファクシンを陽性対照薬とし、強力な三重再取り込み阻害作用( 5-HT、NA及びDA )を有する11個の化合物に対してin vivo抗うつ作用の初歩的研究を行った。 two. In vivo antidepressant results of compounds:
Employing the mouse tail suspension test and the forced swimming test in the `` Learning Despair Test '', using venlafaxine as a positive control drug, a potent triple reuptake inhibitory action (5- An in vivo antidepressant study was conducted on 11 compounds with HT, NA and DA).

1. マウス尾懸垂試験
試験方法：
ICR種のマウス156匹、雄、体重均衡によりランダムで13群に分ける。空白対照群、ベンラファクシン群（20.0 mg・kg-1）、化合物試験群（20.0 mg・kg-1）。10 ml・kg-1 で薬を強制経口投与し、空白対照群には同じ体積の生理塩水を与える。薬を投与して1 時間したら、マウスの尾部から末端約2 cmの箇所を医療用テープで固定し、マウスを尾懸垂ボックス内に逆さまに吊るし、頭部はボックス底から約5 cmほどとする。マウスを2 分吊した後、すぐに観察を開始し、4分間観察を続ける。この4分以内にマウスの無動時間（マウスが空中でもがくのを止める、又は僅かな手足運動しかない）を累計する。改善率は公式で計算して得る： 1. Mouse tail suspension test Test method:
156 ICR mice, male, randomly divided into 13 groups according to weight balance. Blank control group, venlafaxine group (20.0 mg · kg -1 ), compound test group (20.0 mg · kg -1 ). The drug is administered by oral gavage at 10 ml · kg -1 and the blank control group is given the same volume of physiological saline. One hour after the administration of the drug, fix the tip about 2 cm from the tail of the mouse with medical tape, hang the mouse upside down in the tail suspension box, and make the head about 5 cm from the bottom of the box. . After suspending the mouse for 2 minutes, start observation immediately and continue observation for 4 minutes. Within this 4 minutes, the mouse's immobility time (stops struggling in the air or has only a slight limb movement) is accumulated. The improvement rate can be obtained by calculating the formula:

Figure 2013530137
Figure 2013530137

結果は表３を参照：   See Table 3 for results:

Figure 2013530137
Figure 2013530137

マウス尾懸垂試験において、化合物VI-1、VI-2、VI-4、VI-6、VI-13、VI-16、VI-19、VI-36はいずれもマウス尾懸垂無動時間を顕著に短縮し、20mg/kgの薬剤量においてVI-1、VI-2等の8つの化合物の効果は陽性薬ベンラファクシンの同じ薬剤量の際の効果（36.97±21.10s）と類似しており、空白群と比べ明らかな有意差がある。これは前記化合物がいずれも強い体内抗うつ活性を有し、効果がベンラファクシンに類似することを説明している。   In the mouse tail suspension test, compounds VI-1, VI-2, VI-4, VI-6, VI-13, VI-16, VI-19, and VI-36 all show significant mouse tail suspension immobility time. The effect of 8 compounds such as VI-1 and VI-2 at the 20mg / kg drug dose is similar to the effect of the positive drug venlafaxine at the same drug dose (36.97 ± 21.10s) There is a clear significant difference compared to the blank group. This explains that all the compounds have strong in vivo antidepressant activity and the effect is similar to venlafaxine.

2. マウス強制水泳試験
試験方法：
156匹のオスの昆明種マウスを体重均衡ランダム機で13組に分ける。空白対照組、ベンラファクシン組（20.0 mg・kg-1）、化合物試験群（20.0 mg・kg-1）。10 ml・kg-1 で薬を強制経口投与し、空白対照群には同じ体積の生理塩水を与える。試験前日、マウスに対して水泳スクリーニングを行う。マウスを水深10cmのガラス缶内（高さ20cm，直径14cm）に入れ、水温25℃、6分泳がせ、水泳が続かない停止時間が70秒−160秒の間のを正式な試験に用いる。24時間後、再び試験する。薬を投与して1 時間したら、マウス水泳試験を行う。マウスを前記環境で6分泳がせ、6分のうち残りの4分のマウスの水泳停止無動時間を累計する。t検証法を用いてデータを統計学処理する。結果を表4に示す。 2. Mouse forced swimming test Test method:
156 male Kunming mice are divided into 13 groups using a random balance machine. Blank control group, venlafaxine group (20.0 mg · kg -1 ), compound test group (20.0 mg · kg -1 ). The drug is administered by oral gavage at 10 ml · kg -1 and the blank control group is given the same volume of physiological saline. The day before the test, the mice are screened for swimming. The mouse is placed in a glass can with a depth of 10 cm (height 20 cm, diameter 14 cm), allowed to swim for 6 minutes at a temperature of 25 ° C., and the stoppage time during which swimming does not continue is between 70 seconds and 160 seconds. Test again after 24 hours. One hour after administration of the drug, conduct a mouse swimming test. The mouse is allowed to swim for 6 minutes in the above environment, and the immobilization time of the remaining 4 minutes of the mouse in 6 minutes is accumulated. t Statistically process the data using the validation method. The results are shown in Table 4.

Figure 2013530137
Figure 2013530137

マウス強制水泳試験において、測定される化合物はいずれも抗うつ活性を有する。そのうち、化合物VI-1、VI-2、VI-4、VI-13、VI-16、VI-19、VI-22はマウス水泳無動時間を顕著に短縮し、20mg/kgの薬剤量においてVI-1、VI-2等の7つの化合物の効果は陽性薬ベンラファクシンの同じ薬剤量の際の効果と類似しており、空白群と比べ明らかな有意差がある。VI-6、VI-31、VI-36及びVI-46は空白群と比べ明らかな有意差がある。これは前記化合物がいずれも強い体内抗うつ活性を有し、効果がベンラファクシンに類似する又はベンラファクシンよりも強いことを説明している。   In the mouse forced swimming test, any compound to be measured has antidepressant activity. Of these, compounds VI-1, VI-2, VI-4, VI-13, VI-16, VI-19, VI-22 significantly shortened the swimming immobility time of mice, and at a drug dose of 20 mg / kg, VI The effects of 7 compounds such as -1 and VI-2 are similar to those of the positive drug venlafaxine at the same drug amount, and there is a clear significant difference compared with the blank group. VI-6, VI-31, VI-36 and VI-46 are clearly different from the blank group. This explains that all of the compounds have strong in vivo antidepressant activity and the effect is similar to or stronger than venlafaxine.

三．化合物in vivo5-ヒドロキシトリプトファン、ヨヒンビン毒性増強実験及び酸化首振り試験
マウスの5-ヒドロキシトリプトファン（DL-5-HTP）増強作用、マウスのヨヒンビン毒性増強及び酸化首振り試験により、化合物が運動体内において、5−HT、NA及びDA再取り込み阻害作用を有するか否かを確認できる。化合物VI-2を代表として選び、実験する。 three. Compound in vivo 5-hydroxytryptophan, yohimbine toxicity enhancement experiment and oxidation swing test Mouse 5-hydroxytryptophan (DL-5-HTP) potentiating action, mouse yohimbine toxicity enhancement and oxidation swing test, Whether or not 5-HT, NA and DA reuptake inhibitory activity can be confirmed. Choose compound VI-2 as a representative and experiment.

1. VI-2のマウスに対する5-ヒドロキシトリプトファン（DL-5-HTP）増強作用試験（5-Hydroxytryptophan potentiation in mice）
（1） 原理
DL-5-HTPを5-HTの前駆体とし、MAOs阻害剤であるパルギリン(pargyline)はMAOの酵素的分解反応を阻害できる。マウスにおいて特徴性症状頭部痙攣縮反応を観察できる。 1. 5-Hydroxytryptophan potentiation in mice (5-Hydroxytryptophan potentiation in mice)
(1) Principle
With DL-5-HTP as the precursor of 5-HT, the MAOs inhibitor pargyline can inhibit the enzymatic degradation of MAO. Characteristic symptom head spasm response can be observed in mice.

（2）試験方法
VI-2を3つの薬剤量群（30、15、7.5mg/kg）に分け、0.2ml/10g腹腔注射し、30分後、パルギリンを75mg/kg皮下注射し、90分後、DL-5-HTPを静脈注射する。 (2) Test method
Divide VI-2 into three drug dose groups (30, 15, 7.5 mg / kg), 0.2 ml / 10 g intraperitoneally injected, 30 minutes later, pargyline 75 mg / kg subcutaneously, 90 minutes later, DL-5 -Inject HTP intravenously.

（3）結果
30、15及び7.5mg/kgのVI-2は5-HTP作用を明らかに増強した。マウスにおいて明らかな頭部痙攣縮反応が表れた上、この作用は明らかな用量反応関係を呈した。これはVI-2が体内5-HTの再取り込みを確かに阻害できることを説明している（体外結果と一致）。 (3) Results
30, 15, and 7.5 mg / kg VI-2 clearly enhanced 5-HTP action. In addition to the apparent head spasm response in mice, this effect was clearly dose-response related. This explains that VI-2 can certainly inhibit reuptake of 5-HT in the body (in agreement with in vitro results).

Figure 2013530137
Figure 2013530137

2. VI-2のマウスに対するヨヒンビン毒性増強試験（Yohimbine toxicity enhancement in mice）
（1）原理
ヨヒンビンはα2受容体を占め、NAと受容体の結合を阻止する。NA不活性化阻害又はNA再取り込み阻害抗うつ薬により、ヨヒンビンと同時に与えると、NAの濃度が増加するため中毒死する。 2. Yohimbine toxicity enhancement in mice for VI-2 mice
(1) Principle Yohimbine occupies the α 2 receptor and blocks the binding of NA to the receptor. When given simultaneously with yohimbine with NA inactivation inhibition or NA reuptake inhibition antidepressants, the concentration of NA increases and death occurs.

（2）試験方法
ヨヒンビン対照群、VI-2：30、18、11、6.5mg/kg （高薬剤量設計はマウスの5-ヒドロキシトリプトファン増強作用の高薬剤量を参照し、0.6を剤量差とし、下に4つの薬剤量群を設ける）の5つの試験群に分けて実験する。各薬剤群VI-2を1時間（ヨヒンビン対照群にN.Sを与える）経口投与した後、5群全てのマウスにヨヒンビン25mg/kg（動物瀕死薬剤量）を皮下注射し、ヨヒンビン1、2、4、5及び24時間投与した各群の動物死亡率を観察記録し、ED50を計算する。 (2) Test method Yohimbine control group, VI-2: 30, 18, 11, 6.5 mg / kg (For high drug dose design, refer to the high drug dose of mouse 5-hydroxytryptophan potentiating action, 0.6 is the dose difference The test is divided into five test groups (4). After oral administration of each drug group VI-2 for 1 hour (giving NS to the yohimbine control group), yohimbine 25 mg / kg (animal moribund drug amount) was subcutaneously injected to all mice in the five groups, and yohimbine 1, 2, 4 Observe and record animal mortality for each group administered for 5 and 24 hours and calculate ED 50 .

（3）結果
30、18及び11mg/kgのVI-2はヨヒンビンの毒性作用を明らかに増強し、動物の死亡率増加を表した上、この毒性作用は明らかな用量反応関係を呈した。これはVI-2が体内NAの再取り込みを確かに阻害できることを説明している（体外結果と一致）。DASTM統計ソフトによりBliss法計算し、ED50値は32.84mg/kgである。 (3) Results
VI-2 at 30, 18 and 11 mg / kg clearly enhanced the toxic effects of yohimbine, which showed an increase in animal mortality, and this toxic effect showed a clear dose-response relationship. This explains that VI-2 can certainly inhibit reuptake of NA in the body (in agreement with in vitro results). The Bliss method is calculated using DAS TM statistical software, and the ED 50 value is 32.84 mg / kg.

Figure 2013530137
Figure 2013530137

3. 酸化首振り試験
（1）原理
首振り麻痺の発病メカニズムは主にDA機能とAch機能の間の平衡消失と関係し、DA機能の低下やAch機能の高進を引き起こす原因は全て首振りに至る。 3. Oxidation swing test (1) Principle
The pathogenesis of swing paralysis is mainly related to the loss of balance between DA function and Ach function, and all causes of decreased DA function and increased Ach function lead to swing.

酸化首振り剤はM受容体興奮剤であり、首振り、運動失調、流涎、流涙、体温低下などの症状のパーキンソン症候群を招く。   Oxidized swing agents are M receptor stimulants that lead to Parkinson's syndrome with symptoms such as swinging, ataxia, fluency, lacrimation, and hypothermia.

VI-2は体外DA再取り込み阻害試験において、DA再取り込み阻害できることを表した。体内に確かにこの作用があれば、M受容体興奮剤による首振りなどの症状が一部拮抗する。   VI-2 was shown to be able to inhibit DA reuptake in the in vitro DA reuptake inhibition test. If this action is indeed in the body, symptoms such as swinging with M receptor stimulants will partly antagonize.

（2）試験方法
モデル対照群と、VI-2の5つの薬剤量群（300、200、120、60、30mg/kg）の6つの試験群に分けて実験する。各薬剤群VI-2を1時間（モデル対照群にN.Sを与える）経口投与した後、5群全てのマウスに酸化首振り剤（0.5mg/kg，0.1ml/10g）を腹腔注射し、マウスの反応を観察する。 (2) Test method The test is divided into six test groups: a model control group and five drug dose groups of VI-2 (300, 200, 120, 60, 30 mg / kg). After oral administration of each drug group VI-2 for 1 hour (NS is given to the model control group), all mice in the 5 groups were intraperitoneally injected with an oxidized swinging agent (0.5 mg / kg, 0.1 ml / 10 g). Observe the reaction.

（3）結果
酸化首振り剤を5分くらい与え、60匹全てが首振り、カタレプシーなどの現象を表した。 (3) Results
Oxidized swing agent was given for about 5 minutes, and all 60 animals swinged and exhibited catalepsy.

I．首振り： 非常に明らかな用量反応関係を有し、強度は順に、モデル → 30 → 60 → 120 →200 → 300mg/kg。   I. Swing: There is a very clear dose-response relationship, in order of model → 30 → 60 → 120 → 200 → 300 mg / kg.

II．活動性：300mg/kg が最もよく、次が200 → 120 → 60 → 30mg/kg = モデル群。   II. Activity: 300 mg / kg is best, followed by 200 → 120 → 60 → 30 mg / kg = model group.

III．寝返り：300及び200mg/kg VI-2群に程度が異なる寝返り現象が現れ、120mg/kg以下の薬剤量群は基本的にこの症状はなかった。   III. Rolling over: Rolling phenomenon with different degrees appeared in the 300 and 200 mg / kg VI-2 groups, and basically this symptom did not occur in the drug dose group of 120 mg / kg or less.

4. 結果分析
I．VI-2薬剤量の増加に伴い、マウスのカタレプシーが軽減され、首振りも弱くなり、運動性が改善された。30mg/kg薬剤量のとき、首振り抵抗作用はなく、60mg/kgのときも顕著ではない。120mg/kgのとき、首振り症状は改善され、明らかな用量反応関係を呈した。これはVI-2がDAを増強する機能により動物の首振り症状が一部拮抗するが、治療薬剤量（10-20mg/kg）ではDA機能増強作用がない。但しこの弱いDA再取り込み阻害作用は抗うつ作用に有益である可能性があることを説明している。 4. Results analysis
I. As the amount of drug VI-2 increased, the catalepsy of the mice was reduced, the swing was weakened, and the mobility was improved. When the drug amount is 30 mg / kg, there is no resistance to swinging, and it is not significant at 60 mg / kg. At 120 mg / kg, swinging symptoms improved and showed a clear dose-response relationship. This is due to the ability of VI-2 to enhance DA, which partially antagonizes animal swing symptoms, but the therapeutic drug dose (10-20 mg / kg) does not enhance DA function. However, it explains that this weak DA reuptake inhibitory action may be beneficial for antidepressant action.

II．300及び200mg/kg VI-2群の一部に現れた寝返り現象は大溶剤量のVI-2がDAの再取り込みを阻害し、興奮中枢のDAニューロンによるものである。この試験は VI-2体外DA再取り込み阻害作用の証左となった。   II. The rollover phenomenon that appeared in some of the 300 and 200 mg / kg VI-2 groups was due to DA neurons in the excitement center, where large amounts of VI-2 inhibited DA reuptake. This test proved the inhibitory effect of VI-2 in vitro DA reuptake.

四．学習性無力感試験（Learned helplessness）
1. 原理
このモデルは一種の抗うつ動物モデルである。動物を逃げられない嫌な刺激環境におくと、一種の絶望行動が現れ、刺激に対して逃げなくなり、以降の適応性反応を妨げるなどの表現が出る。このとき、動物脳内のカテコールアミンレベルが下がり、これは一種のうつ状態だと公認される。抗うつ薬はこの種の状態に対抗できる。学習性無力感モデルのサブロングペリオド（sub-long period）（3-7d）に使用する各種抗うつ薬には、モノアミン酸化酵素阻害剤、モノアミン再取り込み阻害剤、及び非典型的抗うつ薬の三つが含まれる。 Four. Learning helplessness (Learned helplessness)
1. Principle
This model is a kind of antidepressant animal model. When an animal is placed in an unpleasant stimulus environment where it cannot escape, a kind of despair behavior appears, and it becomes impossible to escape to the stimulus, and expressions such as preventing subsequent adaptive responses appear. At this time, the catecholamine level in the animal brain falls, which is recognized as a kind of depression. Antidepressants can combat this type of condition. The various antidepressants used in the sub-long period (3-7d) of the learned helplessness model include monoamine oxidase inhibitors, monoamine reuptake inhibitors, and atypical antidepressants. Three are included.

2. 実験方法
動物を分け、1日目に逃げられない電気ショックを行う。即ちプレショック動物を用意する。プレショック動物は0.8mA x 15sの脚部電気刺激を受け、毎分1回合計60回行う。対照群のマウスは電気刺激を行わずに箱に入れるだけであり、時間は同じ。 2. Experimental method
Divide the animals and give an electric shock that they cannot escape on the first day. That is, a pre-shock animal is prepared. Pre-shock animals receive 0.8 mA x 15 s electrical stimulation of the leg, 60 times, once a minute. The mice in the control group are simply put in the box without electrical stimulation and the time is the same.

2日目、薬剤を与え始める。薬剤は陽性薬群（ベンラファクシン：30mg/kg）、VI-2：20、10、5mg/kgに分けられ、1週間与え続ける。最後の1回の薬剤投与の後24時間してから条件回避試験を行う。測定指標は回避成功回数と逃避の潜伏期間とする。、   On the second day, start giving the drug. Drugs are divided into positive drug groups (venlafaxine: 30 mg / kg), VI-2: 20, 10, 5 mg / kg, and continue to be given for one week. Condition avoidance test is performed 24 hours after the last single drug administration. The measurement index is the number of successful avoidances and the latent period of escape. ,

3. 結果
正常の対照群の動物は一週間後の条件回避試験において、逃避潜伏期間が明らかに短縮され、回避成功回数は非常に高かった。モデル群の動物は逃げられない電気ショック刺激の後、明らかな絶望行動を表し、逃避潜伏期間は明らかに延長され、回避成功回数は大幅に低下した。ベンラファクシン及び3つの薬剤量のVI-2はいずれも逃避潜伏期間を明らかに短縮し、回避成功回数も明らかに増えた。これはVI-2がうつ状態に対抗できることを説明している。 3. Results The animals in the normal control group had a significantly reduced escape latency in the conditioned avoidance test after one week, and the number of successful escapes was very high. The animals in the model group showed obvious despair behavior after the electric shock stimulus that could not escape, the escape latency period was obviously prolonged, and the number of successful avoidances was greatly reduced. Venlafaxine and the three drug doses VI-2 all significantly shortened the escape latency period and clearly increased the number of successful avoidances. This explains that VI-2 can combat depression.

Figure 2013530137
Figure 2013530137

五．急性毒性試験：張均田監修の《現代薬理実験方法》に記載の方法により、初歩的なスクリーニングを行い、Bliss法で統計し、化合物VI-1、VI-2 及びVI-16のマウスに対する1回経口投与のLD50はそれぞれ1050mg/kg、950mg/kg、870mg/kgである。。 Five. Acute toxicity test: Basic screening by the method described in 《Modern Pharmacological Experiment Method》 supervised by Zhang Chikita, statistical analysis by Bliss method, once oral administration to mice of compounds VI-1, VI-2 and VI-16 The LD 50 for administration is 1050 mg / kg, 950 mg / kg and 870 mg / kg, respectively. .

六．化合物VI-1、VI-2、VI-16の細菌復帰突然変異試験
菌種：チフスサルモネラのヒスチジン栄養欠陥型突然変異株TA97、TA98、TA100、TA102。 Six. Bacterial reverse mutation test of compounds VI-1, VI-2 and VI-16 Species: Typhi salmonella histidine nutrient-deficient mutants TA 97 , TA 98 , TA 100 , TA 102 .

試験方法：文献Maron DM et al: (1983) Mutay Res. 113, 173-216に記載の方法。   Test method: The method described in the document Maron DM et al: (1983) Mutay Res. 113, 173-216.

結果：試験は-S9及び+S9の二つの部分を含み、-S9試験系におけるTA98及び+S9試験系におけるTA97 に対して5000μg/ディシュで抗菌作用を示す。他の薬剤量は全ての菌株に対して抗菌作用を持たず、成長背景が良好である。全ての試験薬剤量は、-S9試験系においても+S9試験系においてもVI-1、VI-2、VI-16全て細菌コロニーの復帰数に明らかな増加をもたらさず、Ames試験は陰性である。 Results: The test comprises two parts -S 9 and + S 9, shows the antibacterial effect on the 5000 [mu] g / dish against TA 97 in TA 98 and + S 9 test system in -S 9 test system. Other drug amounts have no antibacterial action against all strains and have a good growth background. All test drug doses in both the -S 9 and + S 9 test systems did not result in a clear increase in the number of reversions of bacterial colonies VI-1, VI-2, VI-16, and the Ames test was negative It is.

Claims (8)

以下の構造一般式を有する化合物又はその薬学的に許容される塩であることを特徴とするアルキルジアミン類誘導体。
Figure 2013530137
 但し、
Figure 2013530137
 又は、任意的に置換された、チエニル基、フリル基、ピリミジニル基、ピリダジニル基、ピラジニル基、オキサゾール基、イソキサゾール基、チアゾール基、イソチアゾール基、イミダゾール基、ピラゾリルから選択したヘテロアリール基を示し、かつArは未置換ベンゼン環とすることはできない。
R1は水素又はC1−C5のアルキル基を示す。
R2、R3はそれぞれ水素、C1−C5のアルキル基、C1−C5のハロゲン化アルキル基、C1−C5のヒロドキシアルキル基、C1−C5のアルコキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ベンジル基又は置換ベンジル基のうちの一種を示し、かつR2、R3は同時に水素ではない。
又はR2、R3及びNは5員環〜7員環の脂肪環に連なり、該脂肪環に1個のN又はO又はSを含有してもよく、かつNにはR7で置換されてもよい。
R4, R5, R6はそれぞれ水素、C1−C3のアルキル基、C1−C3のアルコキシ基、C1−C3のハロゲン化アルキル基、C1−C3のハロゲン化アルコキシ基、ベンジルオキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ヒドロキシ基、アミノ基、置換アミノ基、ハロゲン、カルボン酸基、カルボン酸エステル基、ニトロ基又はシアノ基のうちの一種を示す。
R7は C1−C5のアルキル基、C1−C5のハロゲン化アルキル基、C1−C5のヒロドキシアルキル基、C1−C5のアルコキシ基、C5又はC6の脂肪環、フェニル基、置換フェニル基、ベンジル基又は置換ベンジル基のうちの一種を示す。
YはC、N、Oを示す。但し、NはC1−C3のアルキル基、C1−C3のハロゲン化アルキル基、C1−C3のヒロドキシアルキル基、フェニル基、置換フェニル基、ベンジル基、置換ベンジル基、芳香族複素環又は置換芳香族複素環で置換できる。
XはC、Nを示す。
ZはC、S、N、Oを含む五員又は六員飽和環、五員又は六員不飽和環を示す。
m = 0、1、2であり、n = 1、 2である。 An alkyldiamine derivative characterized by being a compound having the following general structural formula or a pharmaceutically acceptable salt thereof.
Figure 2013530137
 However,
Figure 2013530137
 Or an optionally substituted thienyl group, furyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, oxazole group, isoxazole group, thiazole group, isothiazole group, imidazole group, pyrazolyl group, And Ar cannot be an unsubstituted benzene ring.
R 1 represents hydrogen or a C 1 -C 5 alkyl group.
R 2 and R 3 are each hydrogen, C 1 -C 5 alkyl group, C 1 -C 5 halogenated alkyl group, C 1 -C 5 hydroxyalkyl group, C 1 -C 5 alkoxy group, One of C 5 or C 6 alicyclic ring, phenyl group, substituted phenyl group, benzyl group or substituted benzyl group is shown, and R 2 and R 3 are not hydrogen at the same time.
Or R 2 , R 3 and N are linked to a 5-membered to 7-membered alicyclic ring, and the alicyclic ring may contain one N, O or S, and N is substituted with R 7 May be.
R 4 , R 5 and R 6 are hydrogen, C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, C 1 -C 3 halogenated alkyl group, C 1 -C 3 halogenated alkoxy, respectively. Group, benzyloxy group, C 5 or C 6 alicyclic ring, phenyl group, substituted phenyl group, hydroxy group, amino group, substituted amino group, halogen, carboxylic acid group, carboxylic acid ester group, nitro group or cyano group A kind of
R 7 is a C 1 -C 5 alkyl group, a C 1 -C 5 halogenated alkyl group, a C 1 -C 5 hydroxyalkyl group, a C 1 -C 5 alkoxy group, a C 5 or C 6 One of an alicyclic ring, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group is shown.
Y represents C, N, or O. However, N is the C 1 -C 3 alkyl group, a halogenated alkyl group of C 1 -C 3, C 1 -C 3 Hiro de alkoxyalkyl group, a phenyl group, a substituted phenyl group, a benzyl group, substituted benzyl group, It can be substituted with an aromatic heterocycle or a substituted aromatic heterocycle.
X represents C and N.
Z represents a 5-membered or 6-membered saturated ring containing C, S, N, or O, or a 5-membered or 6-membered unsaturated ring.
m = 0, 1, 2 and n = 1, 2. 前記置換アミノ基はアミノ基にC1−C3のアルキル基又はC1−C3のハロゲン化アルキル基を有することを特徴とする請求項1に記載のアルキルジアミン類誘導体。 2. The alkyldiamine derivative according to claim 1, wherein the substituted amino group has a C 1 -C 3 alkyl group or a C 1 -C 3 halogenated alkyl group in the amino group. 前記置換フェニル基又は置換ベンジル基はベンゼン環に1〜4個の置換基を有し、その置換基はR4, R5, R6であることを特徴とする請求項1に記載のアルキルジアミン類誘導体。 2. The alkyldiamine according to claim 1, wherein the substituted phenyl group or substituted benzyl group has 1 to 4 substituents on a benzene ring, and the substituents are R 4 , R 5 , R 6. Derivatives. 前記塩は薬学的に許容される無機酸塩又は有機酸塩であることを特徴とする請求項1〜3のいずれか一項に記載のアルキルジアミン類誘導体。   4. The alkyldiamine derivative according to any one of claims 1 to 3, wherein the salt is a pharmaceutically acceptable inorganic acid salt or organic acid salt. 前記塩は0.5-3分子の結晶水を有することを特徴とする請求項4に記載のアルキルジアミン類誘導体。   5. The alkyldiamine derivative according to claim 4, wherein the salt has 0.5-3 molecules of crystal water. 前記化合物は以下を含むことを特徴とする請求項1に記載のアルキルジアミン類誘導体：
VI-1 N,N-ジエチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-2 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-3 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(ピペラジン-1-イル)-プロピルアミン、
VI-4 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン、
VI-5 N-メチル-N-ベンジル-3-(3,4-ジクロロフェニル)-3-モルホリニル-プロピルアミン、
VI-6 4-(3-(3,4-ジクロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン、
VI-7 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-ピペリジニル-プロピルアミン、
VI-8 N,N-ジメチル-3-(4-クロロフェニル)-3-モルホリニル-プロピルアミン、
VI-9 4-(3-(4-クロロフェニル)-3-(ピロリジン-1-イル)プロピル)モルホリン、
VI-10 N,N-ジメチル-3-(4-メチルフェニル)-3-モルホリニル-プロピルアミン、
VI-11 4-(3-(4-メチルピペラジン-1-イル)-1-(4-メチルフェニル)プロピル)モルホリン、
VI-12 4-(3-(4-メチルフェニル)-3-(モルホリニル)プロピル)ピロール、
VI-13 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-14 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-15 N-メチル-3-(ベンゾチオフェン-3-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-16 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-17 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-18 N-メチル-3-(ベンゾチオフェン-3-イル)-3-ピペリジニル-プロピルアミン、
VI-19 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-20 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-21 N-メチル-3-(ベンゾチオフェン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-22 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジン-イル-プロピルアミン、
VI-23 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン、
VI-24 N-メチル-3-(ベンゾチオフェン-2-イル)-3-ピペリジニル-プロピルアミン、
VI-25 N,N-ジメチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-26 N-メチル-N-ベンジル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-27 N-メチル-3-(ベンゾチオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-28 N,N-ジメチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-29 N-メチル-N-ベンジル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-30 N-メチル-3-(ベンゾチオフェン-3-イル)-3-モルホリニル-プロピルアミン、
VI-31 N,N-ジメチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-32 N-メチル-N-ベンジル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-33 N-メチル-3-(インドール-3-イル)-3-モルホリニル-プロピルアミン、
VI-34 N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-モルホリニル-プロピルアミン、
VI-35 N-メチル-N-ベンジル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-モルホリニル-プロピルアミン、
VI-36 N,N-ジメチル-3-(5-クロロ-6-メトキシナフタレン-2-イル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-37 N,N-ジメチル-3-(4-メトキシフェニル)-3-(ピロリジン-1-イル)-プロピルアミン、
VI-38 N,N-ジメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-39 N,N,2-トリメチル-3-(4-メトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-40 N,N-ジメチル-2-((3,4-ジクロロフェニル)(モルホリン)メチル)-1-ヘプチルアミン、
VI-41 N,N-ジメチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-42 N-メチル-N-ベンジル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-43 N-メチル-3-(2,3-ジヒドロベンゾフラン-5-イル)-3-モルホリニル-プロピルアミン、
VI-44 N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-モルホリニル-ブチルアミン、
VI-45 N,N-ジメチル-4-(3,4-ジクロロフェニル)-4-(ピペラジン-1-イル)-ブチルアミン、
VI-46 N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-モルホリニル-ブチルアミン、
VI-47 N,N-ジメチル-4-(ベンゾチオフェン-3-イル)-4-(ピペラジン-1-イル)-ブチルアミン、
VI-48 N,N-ジメチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-49 N-メチル-N-ベンジル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-50 N-メチル-3-(2,4-ジフルオロフェニル)-3-モルホリニル-プロピルアミン、
VI-51 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-ベンジルピペラジニル)-プロピルアミン、
VI-52 N,N-ジメチル-3-(3,4-ジクロロフェニル)-3-(4-(3-(トリフルオロメチル)フェニル)ピペラジニル)-プロピルアミン、
VI-53 N-メチル-N-ベンジル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン、
VI-54 N-メチル-3-(1,2-ベンゾジオキソール-4-イル)-3-ピペリジニル-プロピルアミン、
VI-55 N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-56 N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-57 N-メチル-3-(3,4-ジメトキシフェニル)-3-モルホリニル-プロピルアミン、
VI-58 N,N-ジメチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-59 N-メチル-N-ベンジル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-60 N-メチル-3-(3,4-ジメトキシフェニル)-3-ピペリジニル-プロピルアミン、
VI-61 N,N-ジメチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-62 N-メチル-N-ベンジル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン、
VI-63 N-メチル-3-(チオフェン-2-イル)-3-モルホリニル-プロピルアミン
又はその薬学的に許容される塩。 The alkyldiamine derivative according to claim 1, wherein the compound comprises:
VI-1 N, N-diethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-2 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-3 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (piperazin-1-yl) -propylamine,
VI-4 N, N-dimethyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine,
VI-5 N-methyl-N-benzyl-3- (3,4-dichlorophenyl) -3-morpholinyl-propylamine,
VI-6 4- (3- (3,4-dichlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine,
VI-7 N, N-dimethyl-3- (3,4-dichlorophenyl) -3-piperidinyl-propylamine,
VI-8 N, N-dimethyl-3- (4-chlorophenyl) -3-morpholinyl-propylamine,
VI-9 4- (3- (4-Chlorophenyl) -3- (pyrrolidin-1-yl) propyl) morpholine,
VI-10 N, N-dimethyl-3- (4-methylphenyl) -3-morpholinyl-propylamine,
VI-11 4- (3- (4-methylpiperazin-1-yl) -1- (4-methylphenyl) propyl) morpholine,
VI-12 4- (3- (4-methylphenyl) -3- (morpholinyl) propyl) pyrrole,
VI-13 N, N-dimethyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-14 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-15 N-methyl-3- (benzothiophen-3-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-16 N, N-dimethyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-17 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-18 N-methyl-3- (benzothiophen-3-yl) -3-piperidinyl-propylamine,
VI-19 N, N-dimethyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-20 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-21 N-methyl-3- (benzothiophen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-22 N, N-dimethyl-3- (benzothiophen-2-yl) -3-piperidin-yl-propylamine,
VI-23 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine,
VI-24 N-methyl-3- (benzothiophen-2-yl) -3-piperidinyl-propylamine,
VI-25 N, N-dimethyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-26 N-methyl-N-benzyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-27 N-methyl-3- (benzothiophen-2-yl) -3-morpholinyl-propylamine,
VI-28 N, N-dimethyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-29 N-methyl-N-benzyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-30 N-methyl-3- (benzothiophen-3-yl) -3-morpholinyl-propylamine,
VI-31 N, N-dimethyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-32 N-methyl-N-benzyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-33 N-methyl-3- (indol-3-yl) -3-morpholinyl-propylamine,
VI-34 N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine,
VI-35 N-methyl-N-benzyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3-morpholinyl-propylamine,
VI-36 N, N-dimethyl-3- (5-chloro-6-methoxynaphthalen-2-yl) -3- (pyrrolidin-1-yl) -propylamine,
VI-37 N, N-dimethyl-3- (4-methoxyphenyl) -3- (pyrrolidin-1-yl) -propylamine,
VI-38 N, N-dimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine,
VI-39 N, N, 2-trimethyl-3- (4-methoxyphenyl) -3-morpholinyl-propylamine,
VI-40 N, N-dimethyl-2-((3,4-dichlorophenyl) (morpholine) methyl) -1-heptylamine,
VI-41 N, N-dimethyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-42 N-methyl-N-benzyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-43 N-methyl-3- (2,3-dihydrobenzofuran-5-yl) -3-morpholinyl-propylamine,
VI-44 N, N-dimethyl-4- (3,4-dichlorophenyl) -4-morpholinyl-butylamine,
VI-45 N, N-dimethyl-4- (3,4-dichlorophenyl) -4- (piperazin-1-yl) -butylamine,
VI-46 N, N-dimethyl-4- (benzothiophen-3-yl) -4-morpholinyl-butylamine,
VI-47 N, N-dimethyl-4- (benzothiophen-3-yl) -4- (piperazin-1-yl) -butylamine,
VI-48 N, N-dimethyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-49 N-methyl-N-benzyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-50 N-methyl-3- (2,4-difluorophenyl) -3-morpholinyl-propylamine,
VI-51 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4-benzylpiperazinyl) -propylamine,
VI-52 N, N-dimethyl-3- (3,4-dichlorophenyl) -3- (4- (3- (trifluoromethyl) phenyl) piperazinyl) -propylamine,
VI-53 N-methyl-N-benzyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine,
VI-54 N-methyl-3- (1,2-benzodioxol-4-yl) -3-piperidinyl-propylamine,
VI-55 N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-56 N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-57 N-methyl-3- (3,4-dimethoxyphenyl) -3-morpholinyl-propylamine,
VI-58 N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-59 N-methyl-N-benzyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-60 N-methyl-3- (3,4-dimethoxyphenyl) -3-piperidinyl-propylamine,
VI-61 N, N-dimethyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine,
VI-62 N-methyl-N-benzyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine,
VI-63 N-methyl-3- (thiophen-2-yl) -3-morpholinyl-propylamine or a pharmaceutically acceptable salt thereof. 治療有効量の請求項1〜6のいずれか一項に記載のアルキルジアミン類誘導体および医学的に許容される担体を含有するうつ病治療用組成物。   A composition for treating depression comprising a therapeutically effective amount of the alkyldiamine derivative according to any one of claims 1 to 6 and a medically acceptable carrier. 抗うつ治療薬製造のための請求項1〜6のいずれか一項に記載のアルキルジアミン類誘導体の使用。   Use of the alkyldiamine derivatives according to any one of claims 1 to 6 for the manufacture of an antidepressant drug.
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